Adenosine A3 receptor antagonists

ABSTRACT

A pharmaceutical composition for antagonizing adenosine at adenosine A 3  receptors which comprises a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted is provided and can be used as a prophylactic and therapeutic agent for asthma, allergosis, inflammation, and so on.

This Application is the National Stage of International ApplicationSerial No. PCT/JP98/04837, filed Oct. 26, 1998.

TECHNICAL FIELD

The present invention relates to an agent for antagonizing adenosine atadenosine A₃ receptors and a novel thiazole compound having a superiorantagonistic activity at adenosine A₃ receptor.

BACKGROUND ART

As subtypes of adenosine receptors, A₁, A_(2a), A_(2b) and A₃ are known.Adenosine induces bronchial constriction in asthma patients, whiletheophylline, which is known as an antiasthmatic, antagonizes adenosine.Recently several reports showed that activation of adenosine A3receptors in rats promotes degranulation of mast cells [Journal ofBiological Chemistry, 268, 16887-16890 (1993)], that adenosine A₃receptors exist on peripheral blood eosinophils and that the stimulationof adenosine A₃ receptors activates phospholipase C and elevatesintracellular calcium [Blood, 88, 3569-3574 (1996)].

Currently, as selective A₃ adenosine receptor antagonists, xanthinederivatives are reported in GB-A-2288733 and WO 95/11681, and thefollowing compounds are reported in Journal of Medicinal Chemistry, 40,2596-2608(1997).

The following thiazole compounds are known.

1) A thiazole derivative of the formula:

wherein R¹ represents i) cycloalkyl, ii) cyclic amino, iii) amino whichmay be substituted by 1 or 2 substituents selected from the groupconsisting of lower alkyl, phenyl, acetyl and loweralkoxycarbonylacetyl, iv) alkyl which may be substituted by asubstituent selected from the group consisting of hydroxy, carboxy andlower alkoxycarbonyl or v) phenyl which may be substituted by asubstituent selected from the group consisting of carboxy,2-carboxyethenyl and 2-carboxy-1-propenyl; R² represents pyridyl whichmay be substituted by a lower alkyl; and R³ represents phenyl which maybe substituted by a substituent selected from the group consisting oflower alkoxy, lower alkyl, hydroxy, halogen and methylenedioxy, or asalt thereof, which has analgesic, anti-pyretic, anti-inflammatory,anti-ulcer, thromboxane A₂ (TXA₂) synthetase inhibitory and plateletaggregation inhibiting actions (JP-A-60-58981).

2) A 1,3-thiazole derivative of the formula:

wherein R¹ represents an optionally substituted alkyl, alkenyl, aryl,aralkyl, cycloalkyl, heterocyclic group having carbon as the attachmentpoint or amino; R² represents pyridyl which may be substituted by analkyl; and R³ represents phenyl which may be substituted, or a saltthereof, which has analgesic, anti-pyretic, anti-inflammatory,anti-ulcer, thromboxane A₂ (TXA₂) synthetase inhibitory and plateletaggregation inhibiting actions (JP-A-61-10580).

3) A 1,3-thiazole derivative of the formula:

wherein R¹ represents an optionally substituted alkyl, alkenyl, aryl,aralkyl, cycloalkyl, heterocyclic group having carbon as the attachmentpoint or amino; R² represents pyridyl which may be substituted by analkyl; and R³ represents aryl which may be substituted, or a saltthereof, which has analgesic, anti-pyretic, anti-inflammatory,anti-ulcer, thromboxane A₂ (TXA₂) synthetase inhibitory and plateletaggregation inhibiting actions (U.S. Pat. No. 4,612,321).

4) A compound of the formula:

wherein R¹ is an optionally substituted phenyl, R² is C₁₋₆ alkyl or(CH₂)_(n)Ar, n is 0-2, Ar is an optionally substituted phenyl, R³ ishydrogen or C₁₋₄ alkyl, R⁴ is hydrogen, C₁₋₄ alkyl, etc, R⁵ is hydrogenor C₁₋₄ alkyl, R⁶ is hydrogen, C₁₋₄ alkyl, etc, or salt thereof, whichhas an activity of inhibiting gastric acid secretion (JP-A-07-503023, WO93/15071).

5) A compound of the formula:

wherein R¹ is pyridyl, etc, R² is phenyl, etc, R³ and R⁴ are hydrogen ormethyl, R⁵ is methyl, etc, R⁶ is hydrogen or methyl, etc, or a saltthereof, which is useful as anti-inflammatory and anti-allergic agents(DE-A-3601411).

6) A compound of the formula:

wherein R¹ is lower alkyl substituted by halogen, R² is pyridyl, etc, R³is phenyl, etc, or a salt thereof, which has anti-inflammatory,antipyretic, analgesic and anti-allergic activities (JP-A-5-70446).

From the prior art described above, it is thought that adenosine causesasthma through its binding to adenosine A₃ receptor, therefore A₃adenosine receptor antagonists are expected to become a new type ofantiasthma drug. Accordingly, an agent for antagonizing adenosine atadenosine A₃ receptors which has potent antagonistic activity, goodbioavailability upon administration and good metabolical stability areexpected to have potent therapeutic effects for asthma, inflammation,Addison's diseases, autoallergic hemolytic anemia, Crohn's diseases,psoriasis, rheumatism and diabetes. However, as a prophylactic andtherapeutic agent for adenosine A₃ receptor-related diseases, no goodagents for antagonising adenosine at gadenosine A₃ receptors are knownin terms of potency, safety, bioavailability, and metabolic'stability.Therefore a good agent for antagonising adenosine at adenosine A₃receptor is expected to be developed.

DISCLOSURE OF INVENTION

We, the present inventors, have studied various compounds having anantagonistic activity at adenosine A₃ receptors, and as a result, havefound for the first time that a 1,3-azole compound substituted on the 4-or 5-position, or both, by a pyridyl which may be substituted(hereinafter sometimes referred to briefly as compound (I)], has anunexpected, excellent selective affinity to adenosine A₃ receptor,antagonistic activity at adenosine A₃ receptor and high stability, andis therefore satisfactory as a medicine.

Compound (I) comprises, for example, a compound of the formula:

wherein R¹ represents a hydrogen atom, a hydrocarbon group which may besubstituted, a heterocyclic group which may be substituted, an aminowhich may be substituted or an acyl;

at least one of R² and R³ represents a hydrogen atom, a pyridyl whichmay be substituted or an aromatic hydrocarbon group which may besubstituted, and the other represents a pyridyl which may besubstituted; and

X represents a sulfur atom which may be oxidized, an oxygen atom or agroup of the formula: NR⁴ wherein R⁴ represents a hydrogen atom, ahydrocarbon group which may be substituted or an acyl;

or a salt thereof, which may be N-oxidized [hereinafter sometimesreferred to briefly as compound (Ia)], and a novel compound of theformula:

wherein R^(1a) represents (i) an aromatic heterocyclic group which maybe substituted, (ii) an amino which may be substituted by substituent(s)selected from the group consisting of a substituted carbonyl and ahydrocarbon group which may be substituted, (iii) a cyclic amino whichmay be substituted or (iv) an acyl;

R^(2a) represents an aromatic hydrocarbon group which may besubstituted; and

R^(3a) represents a pyridyl which may be substituted, or a salt thereof[hereinafter sometimes referred to briefly as compound (Ib)] beingwithin the scope of compound (Ia).

On the basis of these findings, the inventors have completed the presentinvention.

Specifically, the present invention relates to:

(1) A pharmaceutical composition for antagonizing adenosine at adenosineA₃ receptors which comprises compound (I);

(2) a composition of the above (1), wherein the 1,3-azole compound iscompound (Ia);

(3) a composition of the above (2), wherein R¹ is

(i) a hydrogen atom,

(ii) a C₁₋₈ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄aryl or C₇₋₁₆ aralkyl group which may be substituted by 1 to 5substituents,

(iii) a 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygenatoms in addition to carbon atoms, which group may be substituted by 1to 5 substituents,

(iv) an amino which may be substituted by 1 or 2 substituents selectedfrom the group consisting of

(a) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄aryl or C₇₋₁₆ aralkyl group which may be substituted by 1 to 5substituents,

(b) a C₁₋₆ alkylidene group which may be substituted by 1 to 5substituents,

(c) a 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygenatoms in addition to carbon atoms, which group may be substituted by 1to 5 substituents, and

(d) an acyl of the formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ wherein R⁵ is (i′) a hydrogen atom, (ii′) a C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆aralkyl group which may be substituted by 1 to 5 substituents or (iii′)a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atomsselected from the group consisting of nitrogen, sulfur and oxygen atomsin addition to carbon atoms, which group may be substituted by 1 to 5substituents; R⁶ is a hydrogen atom or C₁₋₆ alkyl; and R⁷ is (i′) a C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆aralkyl group which may be substituted by 1 to 5 substituents or (ii′) a5- to 14-membered heterocyclic group containing 1 to 4 heteroatomsselected from the group consisting of nitrogen, sulfur and oxygen atomsin addition to carbon atoms, which group may be substituted by 1 to 5substituents,

(v) a 5- to 7-membered non-aromatic cyclic amino optionally containing 1to 4 hetero atoms selected from the group consisting of nitrogen, sulfurand oxygen atoms in addition to carbon atoms and at least one nitrogenatom, which may be substituted by 1 to 3 substituents selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to10-membered aromatic heterocyclic group and oxo, or

(vi) an acyl of the formula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶,—(C═S)—NHR⁵ or —SO₂—R⁷ wherein each symbol is as defined above;

at least one of R² and R³ is

(i) a hydrogen atom,

(ii) a pyridyl which may be substituted by 1 to 5 substituents or

(iii) a C₆₋₁₄ aryl which may be substituted by 1 to 5 substituents inwhich a substituent can form, together with a neighboring substituent, a4- to 7-membered non-aromatic carbocyclic ring;

and the other is a pyridyl which may be substituted by 1 to 5substituents; and

X is a sulfur atom which may be oxidized, an oxygen atom or a group ofthe formula: NR⁴ wherein R⁴ is (i) a hydrogen atom, (ii) a C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents or (iii) an acylof the formula: —(C═O)—R⁵; —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or—SO₂—R⁷ wherein each symbol is as defined above, wherein the above“substituents” are selected from the group consisting of (1) halogenatoms, (2) C₁₋₃ alkylenedioxy, (3) nitro, (4) cyano, (5) optionallyhalogenated C₁₋₆ alkyl, (6) optionally halogenated C₂₋₆ alkenyl, (7)carboxy C₂₋₆ alkenyl, (8) optionally halogenated C₂₋₆ alkynyl, (9)optionally halogenated C₃₋₆ cycloalkyl, (10) C₆₋₁₄ aryl, (11) optionallyhalogenated C₁₋₈ alkoxy, (12) C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, (13)hydroxy, (14) C₆₋₁₄ aryloxy, (15) C₇₋₁₆ aralkyloxy,(16) mercapto, (17)optionally halogenated C₁₋₆ alkylthio, (18) C₆₋₁₄ arylthio, (19) C₇₋₁₆aralkylthio, (20) amino, (21) mono-C₁₋₆ alkylamino, (22) mono-C₆₋₁₄arylamino, (23) di-C₁₋₆ alkylamino, (24) di-C₆₋₁₄ arylamino, (25)formyl, (26) carboxy, (27) C₁₋₆ alkyl-carbonyl, (28) C₃₋₆cycloalkyl-carbonyl, (29) C₁₋₆ alkoxy-carbonyl, (30) C₆₋₁₄aryl-carbonyl, (31) C₇₋₁₆ aralkyl-carbonyl, (32) C₆₋₁₄ aryloxy-carbonyl,(33) C₇₋₁₆ aralkyloxy-carbonyl, (34) 5- or 6-membered heterocyclecarbonyl, (35) carbamoyl, (36) mono-C₁₋₆ alkyl-carbamoyl, (37) di-C₁₋₆alkyl-carbamoyl, (38) C₆₋₁₄ aryl-carbamoyl, (39) 5- or 6-memberedheterocycle carbamoyl, (40) C₁₋₆ alkylsulfonyl, (41) C₆₋₁₄ arylsulfonyl,(42) formylamino, (43) C₁₋₆ alkyl-carbonylamino, (44) C₆₋₁₄aryl-carbonylamino, (45) C₁₋₆ alkoxy-carbonylamino, (46) C₁₋₆alkylsulfonylamino, (47) C₆₋₁₄ arylsulfonylamino, (48) C₁₋₆alkyl-carbonyloxy, (49) C₆₋₁₄ aryl-carbonyloxy, (50) C₁₋₆alkoxy-carbonyloxy, (51) mono-C₁₋₆ alkyl-carbamoyloxy, (52) di-Ci₆alkyl-carbamoyloxy, (53) C₆₋₁₄ aryl-carbamoyloxy, (54) nicotinoyloxy,(55) 5- to 7-membered saturated cyclic amino which may be substituted by1 to 3 substituents selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-membered aromatic heterocyclicgroup and oxo, (56) 5- to 10-membered aromatic heterocyclic group and(57) sulfo;

(4) a composition of the above (2), wherein R¹ is an amino which may besubstituted;

(5) a composition of the above (3), wherein R¹ is an amino which may besubstituted by 1 or 2 acyl of the formula: —(C═O)—R⁵, —(C═O)—OR⁵,—(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷;

(6) a composition of the above (3), wherein R¹ is an amino which may besubstituted by 1 or 2 acyl of the formula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶;

(7) a composition of the above (3), wherein R¹ is a 5- to 7-memberednon-aromatic cyclic amino optionally containing 1 to 4 hetero atomsselected from the group consisting of nitrogen, sulfur and oxygen atomsin addition to carbon atoms and at least one nitrogen atom, which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-membered aromaticheterocyclic group and oxo;

(8) a composition of the above (2), wherein X is S;

(9) a composition of the above (2), wherein R² is a pyridyl which may besubstituted;

(10) a composition of the above (2), wherein R³ is a C₆₋₁₄ aryl whichmay be substituted;

(11) a composition of the above (3), wherein R¹ is an amino which may besubstituted by 1 or 2 acyl of the formula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶;

R² is a pyridyl which may be substituted by 1 to 5 C₁₋₆ alkyl;

R³ is a C₆₋₁₄ aryl which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and carboxy;and

X is S;

(12) a composition of the above (2), wherein R¹ is

(i) a C₁₋₈ alkyl, C₃₋₆ cycloalkyl or C₆₋₁₄ aryl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen atoms, optionally halogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl,optionally halogenated C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy,hydroxy, amino, mono-C-₁₋₆ alkylamino, carboxy, C₁₋₆ alkoxy-carbonyl,mono-C₁₋₆ alkyl-carbamoyl and C₆₋₁₄ aryl-carbonylamino,

(ii) a 5-membered heterocyclic group,

(iii) an amino which may be substituted by 1 or 2 substituents selectedfrom the group consisting of (1) C₁₋₆ alkyl, (2) C₆₋₁₄ aryl, (3) C₇₋₁₆aralkyl,(4) 6-membered heterocyclic group, (5) a C₁₋₆ alkyl-carbonyl,C₃₋₆ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl,C₁₋₆ alkyl-carbamoyl or 5- or 6-membered heterocycle carbonyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkoxy, carboxy and C₁₋₆alkoxy-carbonyl, and (6) di-C₁₋₆ alkylamino-C₁₋₆ alkylidene,

(iv) a 5- or 6-membered non-aromatic cyclic amino which may besubstituted by C₁₋₆ alkyl-carbonyl or oxo, or

(v) carboxy;

R²is a pyridyl which may be substituted by 1 to 3 C₁₋₆ alkyl;

R³ is a C₆₋₁₀ aryl which may be substituted by 1 to 3 substituentsselected from the group consisting of halogen atoms, C₁₋₃ alkylenedioxy,optionally halogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl, optionallyhalogenated C₁₋₈ alkoxy, hydroxy, C₇₋₁₆ aralkyloxy and C₁₋₆alkyl-carbonyloxy, in which the alkyl group can form, together with aneighboring alkyl group, a 5-membered non-aromatic carbocyclic ring; and

X is S;

(13) an adenosine A₃ receptor antagonist which comprises a 1,3-azolecompound substituted on the 4- or 5-position, or both, by a pyridylwhich may be substituted;

(14) a composition of the above (1), which is for preventing and/ortreating asthma or allergosis;

(15) compound (Ib);

(16) a compound of the above (15), wherein R^(1a) is an amino which maybe substituted by 1 or 2 substituents selected from the group consistingof C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₄ aryl-carbonyl and C₁₋₆alkyl-carbamoyl;

R^(2a) is a phenyl which may be substituted by 1 to 3 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl and optionally halogenated C₁₋₆ alkoxy; and

R^(3a) is a pyridyl;

(17) a process for producing compound (Ib), which comprises reacting acompound of the formula:

wherein Hal represents halogen atoms and other symbols are as definedabove, or a salt thereof with a compound of the formula:

wherein R^(1a) is as defined above, or a salt thereof, optionally in thepresence of a base;

(18) a pharmaceutical composition which comprises compound (Ib);

(19) a composition of the above (18) which is an agent for antagonizingadenosine at adenosine A₃ receptors;

(20) a composition of the above (18) which is for preventing and/ortreating asthma or allergosis;

(21) a method for preventing and/or treating diseases related toadenosine A₃ receptor in mammal, which comprises administering to saidmammal an effective amount of a compound of the above (1) or apharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable excipient, carrier or diluent; and

(22) use of a compound of the above (1) or a salt thereof formanufacturing a pharmaceutical composition for preventing and/ortreating diseases related to adenosine A₃ receptor, and so forth.

In this specification, the “acyl” includes, for example, an acyl of theformula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷wherein R⁵ represents a hydrogen atom, a hydrocarbon group which may besubstituted or a heterocyclic group which may be substituted; R⁶represents a hydrogen atom or C₁₋₆ alkyl; and R⁷ represents ahydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted.

In the above formulae, the “hydrocarbon group” of the “hydrocarbon groupwhich may be substituted” for R⁵ includes, for example, an acyclic orcyclic hydrocarbon group such as alkyl, alkenyl, alkynyl, cycloalkyl,aryl, aralkyl, etc. Among them, C₁₋₁₆ acyclic or cyclic hydrocarbongroup is preferable.

The preferred “alkyl” is for example C₁₋₆ alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl, etc.

The preferred “alkenyl” is for example C₂₋₆ alkenyl such as vinyl,allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.

The preferred “alkynyl” is for example C₂₋₆ alkynyl such as ethynyl,propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.

The preferred “cycloalkyl” is for example C₃₋₆ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The preferred “aryl” is for example C₆₋₁₄ aryl such as phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl, etc.

The preferred “aralkyl” is for example C₇₋₁₆ aralkyl such as benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.

Examples of the “substituents” of the “hydrocarbon group which may besubstituted” for R⁵ include halogen atoms (e.g., fluoro, chloro, bromo,iodo, etc.), C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy,etc.), nitro, cyano, optionally halogenated C₁₋₆ alkyl, optionallyhalogenated C₂₋₆ alkenyl, carboxy C₂₋₆ alkenyl (e.g., 2-carboxyethenyl,2-carboxy-2-methylethenyl, etc.), optionally halogenated C₂₋₆ alkynyl,optionally halogenated C₃₋₆ cycloalkyl, C₆₋₁₄ aryl (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl, etc.), optionally halogenated C₁₋₈ alkoxy, C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy, etc.),hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy,etc.), C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy, etc.), mercapto,optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄ arylthio (e.g., phenylthio,1-naphthylthio, 2-naphthylthio, etc.), C₇₋₁₆ aralkylthio (e.g.,benzylthio, phenethylthio, etc.), amino, mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino, etc.), mono-C₆₋₁₄ arylamino (e.g., phenylamino,1-naphthylamino, 2-naphthylamino, etc.), di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino, ethylmethylamino, etc.), di-C₆₋₁₄ arylamino(e.g., diphenylamino, etc.), formyl, carboxy, C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl, etc.), C₃₋₆ cycloalkyl-carbonyl (e.g.,cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl, etc.), C₆₋₁₄ aryl-carbonyl (e.g.,benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl, etc.), C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl, etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-memberedheterocycle carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamroyl, diethylcarbamoyl, ethylmethylcarbamoyl,etc.), C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocycle carbamoyl(e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, etc.), C₆₋₁₄ arylsulfonyl (e.g.,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.),formylamino, C₁₋₆ alkyl-carbonylamino (e.g., acetylamino, etc.), C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino, etc.), C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino,etc.), C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.),di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy, etc.), C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, 5- to7-membered saturated cyclic amino which may be substituted, 5- to10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl, etc.), sulfo, and so forth.

The “hydrocarbon group” may have 1 to 5, preferably 1 to 3 substituentsas mentioned above at possible positions of the hydrocarbon group and,when the number of substituents is two or more, those substituents maybe the same as or different from one another.

The above-mentioned “optionally halogenated C₁₋₆ alkyl” includes, forexample, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may have 1to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo,iodo, etc.). Concretely mentioned is methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.

The above-mentioned “optionally halogenated C₂₋₆ alkenyl” includes, forexample, C₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl, etc.) which may have 1 to 5, preferably 1to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.).

The above-mentioned “optionally halogenated C₂₋₆ alkynyl” includes, forexample, C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl,etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluoro, chloro, bromo, iodo, etc.).

The above-mentioned “optionally halogenated C₃₋₆ cycloalkyl” includes,for example, C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.) which may have 1 to 5, preferably 1 to 3halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Concretelymentioned is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl,etc.

The above-mentioned “optionally halogenated C₁₋₈ alkoxy” includes, forexample, C₁₋₈ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may have1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo,iodo, etc.). Concretely mentioned is methoxy, difluoromethoxy,trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy, etc.

The above-mentioned “optionally halogenated C₁₋₆ alkylthio” includes,for example, C₁₋₆ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro,bromo, iodo, etc.). Concretely mentioned is methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio, etc.

The above-mentioned “5- to 7-membered saturated cyclic amino” of the “5-to 7-membered saturated cyclic amino which may be substituted” includes,for example, 5- to 7-membered saturated cyclic amino optionallycontaining 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur and oxygen atoms in addition to carbon atoms and atleast one nitrogen atom, such as pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, tetrahydroazepin-1-yl, etc.

The “substituents” of the “5- to 7-membered saturated cyclic amino whichmay be substituted” include, for example, 1 to 3 substituents selectedfrom the group consisting of C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl, etc.), and 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), oxo, andso forth.

The “heterocyclic group” of the “heterocyclic group which may besubstituted” for R⁵ includes, for example, a monovalent group formed byremoving an optional hydrogen atom from a 5- to 14-membered (monocyclic,bicyclic or tricyclic) heterocyclic ring containing 1 to 4 hetero atomsof 1 or 2 species selected from the group consisting of nitrogen, sulfurand oxygen atoms in addition to carbon atoms, preferably, (i) a 5- to14-membered, preferably, 5- to 10-membered aromatic heterocyclic ring,(ii) a 5- to 10-membered non-aromatic heterocyclic ring and (iii) a 7-to 10-membered bridged heterocyclic ring, etc.

The above-mentioned “5- to 14-membered, preferably 5- to 10-memberedaromatic heterocyclic ring” includes, for example, an aromaticheterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isoxazole, furazan, phenoxazine, etc.; and a ring asformed through condensation of those. rings, preferably a monocyclicring, with one or more, preferably one or two aromatic rings (e.g.,benzene ring, etc.), etc.

The above-mentioned “5- to 10-membered non-aromatic heterocyclic ring”includes, for example, pyrrolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, morpholine, thiomorpholine,dioxazole, oxadiazoline, oxathiazole, thiadiazoline, triazoline,thiadiazole, dithiazole, etc.

The above-mentioned “7- to 10-membered bridged heterocyclic ring”includes, for example, quinuclidine, 7-azabicyclo[2.2.1]heptane, etc.

Preferable examples of the “heterocyclic group” include, for example, a5- to 14-membered (preferably 5- to 10-membered) (monocyclic orbicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2species selected from the group consisting of nitrogen, sulfur andoxygen atoms in addition to carbon atoms. Concretely mentioned are anaromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl,1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc; and anon-aromatic heterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino,etc.

Among these groups, a 5- or 6-membered heterocyclic group containing 1to 3 hetero atoms selected from the group consisting of nitrogen, sulfurand oxygen atoms in addition to carbon atoms. Concretely mentioned are2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl,3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl,4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl,1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino, etc.

The “substituents” of the “heterocyclic group which may be substituted”are the same as those mentioned above for the “substituents” of the“hydrocarbon group which may be substituted” for R⁵.

The “heterocyclic group” may have 1 to 5, preferably 1 to 3 substituentsas mentioned above at possible positions of the heterocyclic group and,when the number of substituents is two or more, those substituents maybe the same as or different from one another.

The “C₁₋₆ alkyl” for R⁶ includes, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

The “hydrocarbon group which may be substituted” and the “heterocyclicgroup which may be substituted” for R⁷ include, for example, the“hydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” for R⁵ above, respectively.

The “1,3-azole compound” of the “1,3-azole compound substituted on the4- or 5-position, or both, by a pyridyl which may be substituted” in theabove compound (I) includes, for example, 1,3-thiazole, 1,3-oxazole,1,3-imidazole, and so forth.

The “substituents” of the “pyridyl which may be substituted” in the“1,3-azole compound substituted on the 4- or 5-position, or both, by apyridyl which may be substituted” are, for example, the same as thosementioned above for the “substituents” of the “hydrocarbon group whichmay be substituted” for R⁵.

The “pyridyl” may have 1 to 5, preferably 1 to 3 substituents asmentioned above at possible positions thereof and, when the number ofsubstituents is two or more, those substituents may be the same as ordifferent from one another. The ring-constituting nitrogen atom in the“pyridyl” may be oxidized (N-oxidized).

The above-mentioned “1,3-azole compound substituted on the 4- or5-position, or both, by a pyridyl which may be substituted” may furtherhave 1 to 4, preferably 1 to 3 substituents. When the number ofsubstituents is two or more, those substituents may be the same as ordifferent from one another.

Such “substituents” include, for example, a hydrocarbon group which maybe substituted, a heterocyclic group which may be substituted, aminowhich may be substituted, acyl, and so forth.

The above-mentioned “hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” includes, for example, the“hydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” for R⁵ above, respectively.

The above-mentioned “amino which may be substituted” includes, forexample, (1) an amino which may be substituted by 1 or 2 substituentsand (2) a cyclic amino which may be substituted.

The “substituents” of the above (1) “amino which may be substituted by 1or 2 substituents” include, for example, a hydrocarbon group which maybe substituted, a heterocyclic group which may be substituted, acyl,alkylidene which may be substituted, and so forth. The “hydrocarbongroup which may be substituted” and the “heterocyclic group which may besubstituted” include, for example, the “hydrocarbon group which may besubstituted” and the “heterocyclic group which may be substituted” forR⁵ above, respectively.

The above-mentioned “alkylidene” of the “alkylidene which may besubstituted” include, for example, C₁₋₆ alkylidene such as methylidene,ethylidene, propylidene, etc. The “substituents” of the “alkylidenewhich may be substituted” includes, for example, the same as thosementioned above for the “substituents” of the “hydrocarbon group whichmay be substituted” for R⁵. The number of such substituent is 1 to 5,preferably 1 to 3.

When the number of substituents of the above “amino which may besubstituted by 1 or 2 substituents” is two, those substituents may bethe same as or different from one another.

The “cyclic amino” of the above-mentioned (2) “cyclic amino which may besubstituted” includes, for example, 5- to 7-membered non-aromatic cyclicamino optionally containing 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur and oxygen atoms in addition to carbonatoms and at least one nitrogen atom, such as pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl, etc. The “substituents” of the “cyclicamino which may be substituted” include, for example, 1 to 3 of the“substituents” of the “5- to 7-membered saturated cyclic amino which maybe substituted” described in detail in the foregoing referring to the“substituents” of the “hydrocarbon group which may be substituted” forR⁵.

Examples of the 5- to 7-membered non-aromatic cyclic amino substitutedby an oxo are 2-oxoimidazolidin-1-yl,2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl,2-oxo-3,6-dihydro-1(2H)-pyrimidinyl,2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, etc.

Preferable example of compound (I) is compound (Ia).

The ring-constituting nitrogen atom in the 1,3-azole in compound (Ia)may be oxidized (N-oxidized).

The “hydrocarbon group which may be substituted” the “heterocyclic groupwhich may be substituted” and the “amino which may be substituted” forR¹, include, for example, the “hydrocarbon group which may besubstituted” the “heterocyclic group which may be substituted” and the“amino which may be substituted” which the above compound (I) may have,respectively.

R¹ is preferably an amino which may be substituted. More preferred is anamino which may be substituted by 1 or 2 acyl of the formula: —(C═O)—R⁵,—(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ (more preferably,—(C═O)—R⁵ or —(C═O)—NR⁵R⁶) wherein each symbol is as defined above.Among others, especially preferred is a 5- to 7-membered non-aromaticcyclic amino optionally containing 1 to 4 hetero atoms selected from thegroup consisting of nitrogen, sulfur and oxygen atoms in addition tocarbon atoms and at least one nitrogen atom, which may be substituted by1 to 3 substituents selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-membered aromatic heterocyclicgroup and oxo.

The “pyridyl which may be substituted” for R² or R³ includes, forexample, the “pyridyl which may be substituted” which the above compound(I) has.

The “aromatic hydrocarbon group” of the “aromatic hydrocarbon groupwhich may be substituted” for R² or R³ includes, for example, a C₆₋₁₄monocyclic or fused polycyclic (e.g., bi- or tri-cyclic) aromatichydrocarbon group, etc. Concretely mentioned is C₆₋₁₄ aryl such asphenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl, etc.

The “substituents” of the “aromatic hydrocarbon group which may besubstituted” include, for example, the same as those mentioned above forthe “substituents” of the “hydrocarbon group which may be substituted”for R⁵. The number of such substituent is 1 to 5, preferably 1 to 3.When the number of substituents is two or more, those substituents maybe the same as or different from one another. The two substituents(preferably alkyl groups) can form, together with a neighboringsubstituent, a 4- to 7-membered (preferably, 5-membered) non-aromaticcarbocyclic ring.

It is preferred that at least one of R² and R³ is a pyridyl which may besubstituted or an aromatic hydrocarbon group which may be substituted,and the other is a pyridyl which may be substituted.

R² is preferably a pyridyl which may be substituted.

R³ is preferably a C₆₋₁₄ (preferably C₆₋₁₀) aryl which may besubstituted.

The “sulfur atom which may be oxidized” for X includes S, SO and SO₂.

The “hydrocarbon group which may be substituted” for R⁴ includes, forexample, the “hydrocarbon group which may be substituted” for R⁵ above.

X is preferably a sulfur atom which may be oxidized. More preferred isS.

In compound (Ia), preferred is a compound wherein

R¹ is an amino which may be substituted, preferably a monoacylamino;

at least one of R² and R³ is a pyridyl which may be substituted or anaromatic hydrocarbon group which may be substituted, and the other is apyridyl which may be substituted; and

X is S.

More preferred is a compound wherein

R¹ is an amino which may be substituted by 1 or 2 acyl of the formula:—(C═O)—R⁵ or —(C═O)—NR⁵R⁶ wherein each symbol is as defined above;

R² is a pyridyl which may be substituted by 1 to 5 C₁₋₆ alkyl;

R³ is a C₆₋₁₄ aryl which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and carboxy;and

X is S.

Another preferred example is a compound, wherein

R¹ is

(i) a C₁₋₈ alkyl; C₃₋₆ cycloalkyl or C₆₋₁₄ aryl group which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen atoms, optionally halogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl,optionally halogenated C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy,hydroxy, amino, mono-C₁₋₆ alkylamino, carboxy, C₁₋₆ alkoxy-carbonyl,mono-C₁₋₆ alkyl-carbamoyl and C₆₋₁₄ aryl-carbonylamino,

(ii) a 5-membered heterocyclic group,

(iii) an amino which may be substituted by 1 or 2 substituents selectedfrom the group consisting of (1) C₁₋₆ alkyl,(2) C₆₋₁₄ aryl, (3) C₇₋₁₆aralkyl, (4) 6-membered heterocyclic group, (5) a C₁₋₆ alkyl-carbonyl,C₃₋₆ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆ aralkyl-carbonyl,C₁₋₆ alkyl-carbamoyl or 5- or 6-membered heterocycle carbonyl groupwhich may be substituted by 1 to 3 substituents selected from the groupconsisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkoxy, carboxy and C₁₋₆alkoxy-carbonyl, and (6) di-C₁₋₆ alkylamino-C₁₋₆ alkylidene,

(iv) a 5- or 6-membered non-aromatic cyclic amino which may besubstituted by C₁₋₆ alkyl-carbonyl or oxo, or

(v) carboxy;

R² is a pyridyl which may be substituted by 1 to 3 C₁₋₆ alkyl;

R³ is a C₆₋₁₀ aryl which may be substituted by 1 to 3 substituentsselected from the group consisting of halogen atoms, C₁₋₃ alkylenedioxy,optionally halogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl, optionallyhalogenated C₁₋₈ alkoxy, hydroxy, C₇₋₁₆ aralkyloxy and C₁₋₆alkyl-carbonyloxy, and the alkyl group can form, together with theneighboring alkyl group, a 5-membered non-aromatic carbocyclic ring; and

X is S.

More preferred examples of compound (Ia) are

N-[4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-methylpropionamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,

N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-ethylurea,

N-(4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-propylurea,

4-(4-methoxyphenyl)-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-(4-methoxyphenyl)-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-(4-methoxyphenyl)-2-[2-oxotetrahydro-1(2H)-pyrimidinyl)-5-(4-pyridyl)-1,3-thiazole,

4-(4-methoxyphenyl)-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

N-[4-(4-ethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-(4-ethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-methylpropionamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-ethylurea,

N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-propylurea,

4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-[4-(1,1-dimethylethyl)phenyl]-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]-5-(4-pyridyl)-1,3-thiazole,

4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

N-[4-(3,5-dimethylphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-methylpropionamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-ethylurea,

N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-N′-propylurea,

4-(3,5-dimethylphenyl)-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-(3,5-dimethylphenyl)-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,

4-(3,5-dimethylphenyl)-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]-5-(4-pyridyl)-1,3-thiazole,

4-(3,5-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]propionamide,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-2-methylpropionamide,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]benzamide,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]nicotinamide,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-N′-ethylurea,

N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-N′-propylurea,salts thereof, and so forth.

In compound (Ia), compound (Ib) is novel compound.

The “aromatic heterocyclic group” of the “aromatic heterocyclic groupwhich may be substituted” for R^(1a)includes, for example, a monovalentgroup formed by removing an optional hydrogen atom from a 5- to14-membered preferably 5- to 10-membered (monocyclic, bicyclic ortricyclic) aromatic heterocyclic ring containing 1 to 4 hetero atoms of1 or 2 species selected from the group consisting of nitrogen, sulfurand oxygen atoms in addition to carbon atoms, etc. Concretely mentionedare a monovalent group formed by removing an optional hydrogen atom froman aromatic heterocyclic ring such as thiophene, benzo[b]thiophene,benzo[b]furan, benzimidazole, benzoxazole, benzothiazole,benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine,isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, etc.; and aring as formed through condensation of those rings, preferably amonocyclic ring, with one or more, preferably one or two aromatic rings(e.g., benzene ring, etc.), etc.

The preferred example of the “aromatic heterocyclic group” is a 5- or6-membered aromatic heterocyclic group which may be fused with onebenzene ring. Concretely mentioned are 2-thienyl, 3-thienyl, 2-furyl,3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl,1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc. Morepreferred are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-benzothiazolyl, etc.

The “substituents” of the “aromatic heterocyclic group which may besubstituted” and their number are the same as those mentioned above forthe “substituents” of the “hydrocarbon group which may be substituted”for R⁵.

The “amino” of the “amino which may be substituted by substituent(s)selected from the group consisting of a substituted carbonyl and ahydrocarbon group which may be substituted” for R^(1a) includes an aminowhich may be substituted by 1 or 2 substituents selected from the groupconsisting of a substituted carbonyl and a hydrocarbon group which maybe substituted. When the number of substituents is two, thosesubstituents may be the same as or different from one another.

The “substituted carbonyl” of the “amino which may be substituted bysubstituent(s) selected from the group consisting of a substitutedcarbonyl and a hydrocarbon group which may be substituted” includes, forexample, a group of the formula: —(C═O)—R^(5a), —(C═O) OR^(5a) or—(C═O)—NR^(Ra)R^(6a) wherein R^(5a) represents a hydrogen atom, ahydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted, and R^(6a) represents a hydrogen atom or a C₁₋₆alkyl.

The “hydrocarbon group which may be substituted” and the “heterocyclicgroup which may be substituted” for R^(5a) include, for example, the“hydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” for R⁵ above, respectively.

The “C₁₋₆ alkyl” for R^(6a) includes, for example, the “C₁₋₆ alkyl” forR⁶ above.

The examples of the “substituted carbonyl” are formyl carboxy, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C₃₋₆ cycloalkyl-carbonyl(e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,etc.), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl, etc.), C₆₋₁₄ aryl-carbonyl (e.g.,benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl, etc.), C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl, etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-memberedheterocycle carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.),C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocycle carbamoyl(e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), etc.

The “hydrocarbon group which may be substituted” of the “amino which maybe substituted by substituent(s) selected from the group consisting of asubstituted carbonyl and a hydrocarbon group which may be substituted”for R^(1a) includes, for example, the “hydrocarbon group which may besubstituted” for R⁵.

The “cyclic amino which may be substituted” for R^(1a) includes, forexample, the “cyclic amino which may be substituted” described in the“amino which may be substituted” for R¹.

R^(1a) is preferably an amino which may be substituted by substituent(s)selected from the group consisting of a substituted carbonyl and ahydrocarbon group which may be substituted.

The “aromatic hydrocarbon group which may be substituted” for R^(2a)includes, for example, the “aromatic hydrocarbon group which may besubstituted” for R² or R³ above.

The “pyridyl which may be substituted” for R^(3a) includes, for example,the “pyridyl which may be substituted” which the above compound (I) has.

Preferred example of compound (Ib) is a compound wherein

R^(1a) is an amino which may be substituted by 1 or 2 substituentsselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkyl-carbonyl,C₆₋₁₄ aryl-carbonyl and C₁₋₆ alkyl-carbamoyl;

R^(2a) is a phenyl which may be substituted by 1 to 3 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl and optionally halogenated C₁₋₆ alkoxy; and

R^(3a) is a pyridyl.

The examples of compound (Ib) are

N-methyl[5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine,

[5-phenyl-4-(3-pyridyl)thiazol-2-yl]amine,

N-[5-phenyl-4-(3-pyridyl)thiazol-2-yl]acetoamide,

N-[5-[4-(1,1-dimethylethyl)phenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,

N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,

N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,

N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,salts thereof, and so forth.

A novel compound of the formula:

wherein R^(1b) represents a hydrogen atom, a hydrocarbon group which maybe substituted, a heterocyclic group which may be substituted, an aminowhich may be substituted or an acyl;

R^(2b) represents a N-oxidized pyridyl which may be substituted; and

R^(3b) represents a hydrogen atom, a pyridyl which may be substituted oran aromatic hydrocarbon group which may be substituted; or a saltthereof, [hereinafter sometimes referred to briefly as compound (Ic)] isalso within a scope of compound (Ia).

The “hydrocarbon group which may be substituted” the “heterocyclic groupwhich may be substituted” the “amino which may be substituted” and the“acyl” for R^(1b) include, for example, the “hydrocarbon group which maybe substituted” the “heterocyclic group which may be substituted” the“amino which may be substituted” and the “acyl” for R¹ above,respectively.

R^(1b) is preferably an amino which may be substituted. More preferredis an amino which may be substituted by 1 or 2 acyl of the formula:—(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ (morepreferably, —(C═O)—R⁵ or —(C═O)—NR⁵R⁶) wherein each symbol is as definedabove.

The “substituents” of the “N-oxidized pyridyl which may be substituted”are the same as those mentioned above for the “substituents” of the“hydrocarbon group which may be substituted” for R⁵ above. The“N-oxidized pyridyl” may have 1 to 4, preferably 1 to 3 substituents asmentioned above at possible positions of the pyridyl and, when thenumber of substituents is two or more, those substituents may be thesame as or different from one another.

The “pyridyl which may be substituted” and the “aromatic hydrocarbongroup which may be substituted” for R^(3b) include, for example, the“pyridyl which may be substituted” and the “aromatic hydrocarbon groupwhich may be substituted” for R³ above, respectively.

R^(3b) is preferably a C₆₋₁₄ (preferably C₆₋₁₀) aryl which may besubstituted.

A perferred example of compound (Ic) is a compound wherein

R^(1b) is an amino which may be substituted by 1 or 2 acyl of theformula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶ wherein each symbol is as definedabove;

R^(2b) is a N-oxidized pyridyl which may be substituted by 1 to 3 C₁₋₆alkyl; and

R^(3b) is a C₆₋₁₀ aryl which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and carboxy.

The examples of compound (Ic) are

3-[2-acetylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,

4-[2-acetylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,

4-[4-(4-methoxyphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(4-methoxyphenyl)-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-butyrylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,

4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,

4-[4-(4-methoxyphenyl)-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-(N′-ethylureido)-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(4-methoxyphenyl)-2-(N′-propylureido)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-acetylamino-4-(4-ethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,

4-[4-(4-ethylphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine 1-oxide,

3-[2-acetylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-acetylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-[4-(1,1-dimethylethyl)phenyl]-2-propionylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-[4-(1,1-dimethylethyl)phenyl]-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-butyrylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-benzoylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-[4-(1,1-dimethylethyl)phenyl]-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-[4-(1,1-dimethylethyl)phenyl]-2-(N′-ethylureido)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-4-(1,1-dimethylethyl)phenyl]-2-(N′-propylureido)-1,3-thiazol-5-yl]pyridine1-oxide,

3-[2-acetylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-acetylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(3,5-dimethylphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(3,5-dimethylphenyl)-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-butyrylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-benzoylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(3,5-dimethylphenyl)-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine1-oxide,

4-[4-(3,5-dimethylphenyl)-2-(N′-ethylureido)-1,3-thiazol-5-yl]pyridine1-oxide,

4-(4-(3,5-dimethylphenyl)-2-(N′-propylureido)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-acetylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-propionylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-(2-methylpropionyl)amino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-butyrylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-benzoylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-nicotionylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-(N′-ethylureido)-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide,

4-[2-(N′-propylureido)-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine1-oxide, and so forth.

Salts of compound (I), compound (Ia), compound (Ib) or compound (Ic)include, for example, metal salts, ammonium salts, salts with organicbases, salts with inorganic acids, salts with organic acids, salts withbasic or acidic amino acids, etc. Preferred examples of metal saltsinclude alkali metal salts such as sodium salts, potassium salts;alkaline earth metal salts such as calcium salts, magnesium salts,barium salts; aluminium salts, etc. Preferred examples of salts withorganic bases include salts with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, etc. Preferred examples of salts withinorganic acids include hydrochlorides, hydrobromides, nitrates,sulfates, phosphates, etc. Preferred examples of salts with organicacids include formates, acetates, trifluoroacetates, fumarates,oxalates, tartrates, maleates, citrates, succinates, malates,methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.Preferred examples of salts with basic amino acids include salts witharginine, lysine, ornithine, etc. Preferred examples of salts withacidic amino acids include aspartates, glutamates, etc.

Among others, more preferred are pharmaceutically acceptable salts. Forexample, for the compound having an acidic functional group in themolecule, mentioned are their inorganic salts, such as alkali metalsalts (e.g., sodium salts, potassium salts, etc.), and alkaline earthmetal salts (e.g., calcium salts, magnesium salts, barium salts, etc.),ammonium salts, etc.; and for the compound having a basic functionalgroup in the molecule, mentioned are their inorganic salts such ashydrobromides, nitrates, sulfates, phosphates, etc., and organic saltssuch as acetates maleates, fumarates, succinates, citrates, tartrates,methanesulfonates, p-toluenesulfonates, etc.

Process for producing compound (I) (including compounds (Ia), (Ib) and(Ic)) is mentioned below.

Compound (I) can be produced in any per se known manner, for example,according to the methods of the following processes 1 to 3 or analogousmethods thereto as well as the methods disclosed in WO 95/13067 oranalogous methods thereto in case that compound (I) is 1,3-oxazolecompounds, the methods disclosed in U.S. Pat. No. 3,940,486, WO88/01169, WO 93/14081, WO 95/02591, WO 97/12876 or analogous methodsthereto in case that compound (I) is 1,3-imidazole compounds, and themethods disclosed in JP-A-60-58981, JP-A-61-10580, JP-A-7-503023, WO93/15071, DE-A-3601411, JP-A-5-70446 or analogous methods thereto incase that compound (I) is 1,3-thiazole.

Each symbol in the compounds in the following processes 1 to 3 is sameas defined above. The compounds described in the following processesinclude their salts. For their salts, for example, referred to are thesame as the salts of compound (I).

Process 1

Compounds (II), (III), (V), (VII), (XI), (XIII) and (XIV) may bepurchased from commercial sources if they are available on the market orcan be produced in any per se known manner.

Compound (IV) is produced by subjecting compound (II) to condensationwith compound (III) in the presence of a base.

In compound (III), R⁸ represents, for example, (i) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, etc.), (ii) di-C₁₋₆ alkylamino (e.g., dimethylamino,diethylamino, etc.), (iii) N-C₆₋₁₀ aryl-N-C₁₋₆ alkylamino (e.g.,N-phenyl-N-methylamino, etc.), (iv) 3- to 7-membered cyclic amino 15(e.g., pyrrolidino, morpholino, methylaziridin-1-yl, etc.) which may besubstituted by C₆₋₁₀ aryl and/or C₁₋₆ alkyl, etc.

The amount of compound (III) to be used is 0.5 to 3.0 mols or so,preferably 0.8 to 2.0 mols or so, relative to one mol of compound (II).

The amount of the base to be used is 1.0 to 30 mols or so, preferably1.0 to 10 mols or so, relative to one mol of compound (II).

The “base” includes, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, etc.; inorganic bases such assodium hydroxide, potassium hydroxide, etc.; aromatic amines suchaspyridine, lutidine, etc.; tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; metal amides such assodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,etc.; metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, water, and mixtures of thosesolvents.

The reaction temperature is generally −5 to 200° C. or so, preferably 5to 150° C. or so. The reaction time is generally about 5 minutes to 72hours, preferably about 0.5 to 30 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (VIII) is produced by treating compound (IV) with an acid.

The amount of the acid to be used is 1.0 to 100 mols or so, preferably1.0 to 30 mols or so, relative to one mol of compound (IV).

The “acids” include, for example, mineral acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, etc.

This reaction is advantageously carried out in an inert solvent. Thereis no particular limitation on the kind of solvent that can be usedunless the reaction is interfered with. Preferred are water, mixtures ofwater and amides, mixtures of water and alcohols, etc.

The reaction temperature is generally 20 to 200° C. or so, preferably 60to 150° C. or so. The reaction time is generally about 30 minutes to 72hours, preferably about 1 to 30 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (VIII) is also produced by treating compound (V) with a basefollowed by subjecting the resultant compound (VI) to condensation withcompound (VII).

In compound (VI), M represents, for example, an alkali metal such aslithium, sodium, potassium, etc.

In compound (VII), R⁹ represents, for example, same as those mentionedabove for R⁸.

The amount of the base to be used is 1.0 to 30 mols or so, preferably1.0 to 10 mols or so, relative to one mol of compound (V).

The “base” includes, for example, metal amides such as sodium amide,lithium diisopropylamide, lithium hexamethyldisilazide, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are aliphatic hydrocarbons, aromatic. hydrocarbons, ethers,and mixtures of those solvents.

The reaction temperature is generally −78 to 60° C. or so, preferably−78 to 20° C. or so. The reaction time is generally about 5 minutes to24 hours, preferably about 0.5 to 3 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (IX) is produced by treating compound (VIII) with a halogen. Ifdesired, this reaction is carried out in the presence of a base or abasic salt.

The amount of the halogen to be used is 1.0 to 5.0 mols or so,preferably 1.0 to 2.0 mols or so, relative to one mol of compound(VIII).

The “halogen” includes, for example, bromine, chlorine, iodine, etc.

The amount of the base to be used is 1.0 to 10.0 mols or so, preferably1.0 to 3.0 mols or so, relative to one mol of compound (VIII).

The “base” includes, for example, aromatic amines such as pyridine,lutidine, etc.; tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc.

The amount of the basic salt to be used is 1.0 to 10.0 mols or so,preferably 1.0 to 3.0 mols or so, relative to one mol of compound(VIII).

The “basic salt” includes, for example, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate,potassium acetate, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons,amides, halogenated hydrocarbons, nitrites, sulfoxides, organic acids,aromatic amines and mixtures of those solvents.

The reaction temperature is −20 to 150° C. or so, preferably 0 to 100°C. or so. The reaction time is generally 5 minutes to 24 hours,preferably about 10 minutes to 5 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (Ia) is produced by subjecting compound (IX) to condensationwith compound (X). If desired, this reaction is carried out in thepresence of a base or a basic salt.

In compound (IX), Hal represents halogens.

Compound (X) may be purchased from commercial sources if they areavailable on the market or can be produced according to any per se knownmethods or analogous methods thereto as well as the methods disclosed inthe following process 2.

The amount of compound (X) to be used is 0.5 to 3.0 mols or so,preferably 0.8 to 2.0 mols or so, relative to one mol of compound (IX).

The amount of the base to be used is 1.0 to 30 mols or so, preferably1.0 to 10 mols or so, relative to one mol of compound (IX).

The “base” includes, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydrogencarbonate, etc.;aromatic amines such as pyridine, lutidine, etc.; tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, nitrites and mixtures of thosesolvents.

The reaction temperature is −5 to 200° C. or so, preferably 5 to 150° C.or so. The reaction time is generally 5 minutes to 72 hours, preferablyabout 0.5 to 30 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Process 2

Compound (XII) is produced by subjecting compound (XI) to condensationwith an amine of the formula: R¹¹H.

R¹¹ represents the “amine which may be substituted” for R¹ above.

In compound (XI), R¹⁰ represents an alkoxy. The “alkoxy” includes, forexample, a C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc.

The amount of the “amine” to be used is 1.0 to 30 mols or so, preferably1.0 to 10 mols or so, relative to one mol of compound (XI).

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.

Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, amides, alcohols, nitrites, ketones andmixtures-of those solvents. The reaction temperature is −5 to 200° C. orso, preferably 5 to 120° C. or so. The reaction time is generally 5minutes to 72 hours, preferably about 0.5 to 30 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (X) is produced by subjecting compound (XII) to hydrolysisusing an acid or a base.

The amount of the “acid” or “base” to be used is 0.1 to 50 mols or so,preferably 1 to 20 mols or so, relative to one mol of compound (XII),respectively.

The “acid” includes, for example, mineral acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, etc; Lewis acids such as borontrichloride, boron tribromide, etc; thiols or sulfides in combinationwith Lewis acids; organic acids such as trifluoroacetic acid,p-toluenesulfonic acid, etc.

The “base” includes, for example, metal hydroxides such as sodiumhydroxide, potassium hydroxide, barium hydroxide, etc.; metal alkoxidessuch as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc;organic bases such as triethylamine, imidazole, formamidine, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are alcohols, ethers, aromatic hydrocarbons, aliphatichydrocarbons, halogenated hydrocarbons, sulfoxides, water and mixturesof those solvents.

The reaction time is generally 10 minutes to 50 hours, preferably about30 minutes to 12 hours. The reaction temperature is 0 to 200° C. or so,preferably 20 to 120° C. or so.

Compound (X) is also produced by treating compound (XIII) with ahydrogen sulfide in the presence of a base.

The amount of the hydrogen sulfide to be used is 1 to 30 mols or so,relative to one mol of compound (XIII).

The amount of the “base” to be used is 1.0 to 30 mols or so, preferably1.0 to 10 mols or so, relative to one mol of compound (XIII).

The “base” includes, for example, aromatic amines such as pyridine,lutidine, etc.; tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is. no particular limitation on the kindof solvent that can be used unless the reaction is interfered with.Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, ethers, aromatic amines and mixtures of those solvents.

This reaction is carried out under atmospheric pressure or pressurizedcondition. The reaction temperature is −20 to 80° C. or so, preferably−10 to 30° C. or so. The reaction time is generally 5 minutes to 72hours, preferably about 0.5 to 30 hours.

The product as produced in the manner mentioned above may be applied tothe next reaction while it is still crude in the reaction mixture, ormay be isolated from the reaction mixture in any ordinary manner. Thiscan be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Compound (X) is also produced by treating compound (XIV) with aphosphorous pentasulfide or Lawesson's reagent.

The amount of the “phosphorous pentasulfide” or “Lawesson's reagent” tobe used is 0.5 to 10 mols or so, preferably 0.5 to 3 mols or so,relative to one mol of compound (XIV).

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons,halogenated hydrocarbons and mixtures of n those solvents.

The reaction time is generally 10 minutes to 50 hours, preferably about30 minutes to 12 hours. The reaction temperature is 0 to 150° C. or so,preferably 20 to 120° C. or so.

The product (X) may be applied to the next reaction while it is stillcrude in the reaction mixture, or may be isolated from the reactionmixture in any ordinary manner. This can be easily purified throughseparation means such as recrystallization, distillation, chromatographyand the like.

In case that compound (Ia) is an acylamino derivative, the desiredproduct can be also obtained by subjecting the corresponded aminecompound to any per se known acylation method.

For example, compound (Ia) wherein R¹ is an acylamino which may besubstituted is produced by reacting a corresponding 2-thiazolyl aminewith an acylating agent optionally in the presence of a base or an acid.

The amount of the “acylating agent” to be used is 1.0 to 5.0 mols or so,preferably 1.0 to 2.0 mols or so, relative to one mol of compound (Ia).

The “acylating agent” includes, for example, carboxylic acid or areactive derivative thereof (e.g., acid halides, acid anhydrides,esters, etc.) corresponding to the desired product.

The amount of the “base” or “acid” to be used is 0.8 to 5.0 mols or so,preferably 1.0 to 2.0 mols or so, relative to one mol of compound (Ia).

The “base” includes, for example, triethylamine, pyridine,N,N-dimethylamino pyridine, etc.

The “acid” includes, for example, methanesulfonic acid,p-toluenesulfonic acid, camphor-sulfonic acid etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons,amides, halogenated hydrocarbons, nitrites, sulfoxides, aromatic aminesand mixtures of those solvents.

The reaction temperature is −20 to 150° C. or so, preferably 0 to 100°C. or so. The reaction time is generally 5 minutes to 24 hours,preferably about 10 minutes to 5 hours.

The product may be applied to the next reaction while it is still crudein the reaction mixture, or may be isolated from the reaction mixture inany ordinary manner. This can be easily purified through separationmeans such as recrystallization, distillation, chromatography and thelike.

Compound (Ic) can be also produced according to the methods of thefollowing process 3 or analogous methods thereto.

Process 3

Compound (XV) can be produced according to any per se known methods oranalogous methods thereto.

Compound (Ic) is produced by treating compound (XV) with a peroxy acid.

In compound (XV), R^(2b)′ represents a pyridyl which may be substituted.The “pyridyl which may be substituted” includes, for example, the“pyridyl which may be substituted” for R² above.

The amount of the “peroxy acid” to be used is 0.8 to 10 mols or so,preferably 1.0 to 3.0 mols or so, relative to one mol of compound (XV).

The “peroxy acid” includes, for example, peracetic acid,trifluoroperacetic acid, m-chloroperbenzoic acid, etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitriles, ketones and mixtures of those solvents.

The reaction temperature is −20 to 130° C. or so, preferably 0 to 100°C. or so. The reaction time is generally 5 minutes to 72 hours,preferably about 0.5 to 12 hours.

Compound (Ic) is also produced by treating compound (XV) with a hydrogenperoxide or an alkylhydroperoxide, in the presence of a base, an acid ora metal oxide if desired.

The amount of the “hydrogen peroxide” or the “alkylhydroperoxide” to beused is 0.8 to 10 mols or so, preferably 1.0 to 3.0 mols or so, relativeto one mol of compound (XV).

The “alkylhydroperoxide” includes, for example, tert-butylhydroperoxide,cumene hydroperoxide, etc.

The amount of the “base” the “acid” or the “metal oxides” to be used is0.1 to 30 mols or so, preferably 0.8 to 5 mols or so, relative to onemol of compound (XV).

The “base” includes, for example, inorganic bases such as sodiumhydroxide and potassium hydroxide, basic salts such as sodium carbonateand potassium carbonate, etc.

The “acid” includes, for example, mineral acids such as hydrochloricacid, sulfuric acid and perchloric acid, Lewis acids such as borontrifluoride and aluminum (III) chloride, titanium(IV) chloride, organicacids such as formic acid and acetic acid, etc.

The “metal oxides” includes, for example, vanadium oxide (V₂O₅), osmiumoxide (OSO₄), tungsten oxide (WO₃), molybdenum oxide (MoO₃), seleniumoxide (SeO₂), chromium oxide (CrO₃), etc.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatichydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols,nitrites, ketones and mixtures of those solvents.

The reaction temperature is −20 to 130° C. or so, preferably 0 to 100°C. or so. The reaction time is generally 5 minutes to 72 hours,preferably about 0.5 to 12 hours.

The product may be applied to the next reaction while it is still crudein the reaction mixture, or may be isolated from the reaction mixture inany ordinary manner. This can be easily purified through separationmeans such as recrystallization, distillation, chromatography and thelike.

In the above-mentioned reactions where the starting compounds aresubstituted by any of amino, carboxy or hydroxy, those groups may beprotected by ordinary protective groups which are generally used inpeptide chemistry. The protective groups may be removed after thereaction to give the desired products.

The amino-protecting group includes, for example, formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted,phenylcarbonyl which may be substituted, C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, etc.) which may be substituted,phenyloxycarbonyl which may be substituted, C₇₋₁₀ aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, etc.) which may be substituted, trityl whichmay be substituted, phthaloyl which may be substituted, etc. Thesesubstituents include, for example, halogen atoms (e.g., fluoro, chloro,bromo, iodo, etc.), C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,valeryl, etc.), nitro, etc. The number of those substituents is 1 to 3.

The carboxy-protecting group includes, for example, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may besubstituted, phenyl which may be substituted, trityl which may besubstituted, silyl which may be substituted, etc. These substituentsinclude, for example, halogen atoms (e.g., fluoro, chloro, bromo, iodo,etc.), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,butylcarbonyl, etc.), nitro, C₁₋₆ alkyl (e.g., methyl, ethyl,tert-butyl, etc.), C₆₋₁₀ aryl (e.g., phenyl, naphthyl, etc.), etc. Thenumber of those substituents is 1 to 3.

The hydroxy-protecting group includes, for example, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may besubstituted, phenyl which may be substituted, C₇₋₁₁ aralkyl (e.g.,benzyl, etc.) which may be substituted, formyl which may be substituted,C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may besubstituted, phenyloxycarbonyl which may be substituted, C₇₋₁₁aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may besubstituted, tetrahydropyranyl which may be substituted,tetrahydrofuranyl which may be substituted, silyl which may besubstituted, etc. Those substituents include, for example, halogen atoms(e.g., fluoro, chloro, bromo, lodo, etc.), C₁₋₆ alkyl (e.g., methyl,ethyl, tert-butyl, etc.), C₇₋₁₁ aralkyl (e.g., benzyl, etc.), C₆₋₁₀aryl(e.g., phenyl, naphthyl, etc.), nitro, etc. The number of thosesubstituents is 1 to 4.

Those protective groups may be removed by any per se known methods oranalogous methods thereto, such as methods using acids, bases,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,etc.; and reduction, etc.

In any case, products formed in the reaction mixtures may be subjectedto deprotection, acylation, alkylation, hydrogenation, oxidation,reduction, chain extension, substituents-exchange reaction and combinedreactions thereof, to obtain compound (I). These methods include, forexample, the methods described in “Shin Jikken Kagaku Kouza (New Editionof Lectures of Experimental Chemistry)” 14, 15 (1977) edited by Maruzen.

The above “alcohols” include, for example, methanol, ethanol, propanol,isopropanol, tert-butanol, etc.

The above “ethers” include, for example, diethyl ether, diisopropylether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc.

The above “halogenated hydrocarbons” include, for example,dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride,etc.

The above “aliphatic hydrocarbons” include, for example, hexane,pentane, cyclohexane, etc.

The above “aromatic hydrocarbons” include, for example, benzene,toluene, xylene, chlorobenzene, etc.

The above “aromatic amines” include, for example, pyridine, lutidine,quinoline, etc.

The above “amides” include, for example, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.

The above “ketones” include, for example, acetone, methyl ethyl ketone,etc.

The above “sulfoxides” include, for example, dimethylsulfoxide, etc.

The above “nitrites” include, for example, acetonitrile, propionitrile,etc.

The above “organic acids” include, for example, acetic acid, propionicacid, trifluoroacetic acid, etc.

Where the products are formed in their free form in the reaction, theymay be converted into their salts in any ordinary manner. Where they areformed in the form of their salts, they may be converted into freecompounds or other salts in any ordinary manner. The thus-obtainedcompound (I) may be isolated and purified from the reaction mixturesthrough any ordinary means of, for example, trans-solvation,concentration, solvent extraction, fractionation, crystallization,recrystallization, chromatography and the like.

Where compound (I), (Ia), (Ib) or (Ic) exists in the reaction mixturesin the form of its configurational isomers, diastereomers, conformers orthe like, they may be optionally isolated into single isomers throughthe separation and isolation means mentioned above. Where compound (I),(Ia), (Ib) or (Ic) is in the form of its racemates, they may be resolvedinto S- and R-forms through any ordinary optical resolution.

Compound (I), (Ia), (Ib) or (Ic) includes stereoisomers, depending onthe type of the substituents therein, and both single isomers andmixtures of different isomers are within the scope of the presentinvention.

Compounds (I), (Ia), (Ib) and (Ic) may be in any form of their hydratesand non-hydrates.

The agent (pharmaceutical composition) of the. present inventioncomprising compound (I), (Ia), (Ib) or (Ic) shows a high affinity foradenosine receptor, especially for adenosine A₃ receptor, while havinglow toxicity and few side effects. The agent is useful as a safemedicine.

The agent (pharmaceutical composition) of the present inventioncomprising compound (I), (Ia), (Ib) or (Ic) has a potent antagonisticactivity on mammals (e.g., mouse, rat, hamster, rabbit, feline, canine,bovine, sheep, monkey, human, etc.), a good bioavailability uponadministration, a good metabolical stability, and therefore, it can beused for preventing and/or treating diseases that may be related toadenosine A₃ receptor, for example, asthma, allergosis, inflammation,Addison's disease, autoallergic hemolytic anemia, Crohn's disease,psoriasis, rheumatism, diabetes, and so on. Among others, preferred isfor asthma, allergosis, etc.

The agent (pharmaceutical composition) of the present inventioncomprising compound (I), (Ia), (Ib) or (Ic) has low toxicity, andtherefore, compound (I), (Ia), (Ib) or (Ic) is, either directly as it isor after having been formulated into pharmaceutical compositions alongwith pharmaceutically acceptable carriers in any per se known manner,for example, into tablets (including sugar-coated tablets, film-coatedtablets), powders, granules, capsules (including soft capsules), liquidpreparations, injections, suppositories, sustained release preparations,etc., safely administered orally or parenterally (e.g., locally,rectally, intravenously, etc.). In the pharmaceutical composition of thepresent invention, the amount of compound (I), (Ia), (Ib) or (Ic) isfrom 0.01 to 100% by weight or so of the total weight of thecomposition. The dose of the composition varies, depending on thesubject to which the composition is administered, the administrationroute employed, the disorder of the subject, etc. For example, as anadenosine A₃ receptor antagonist, oral composition for treating asthma,its dose for adults (body weight ca. 60 kg) may be from 0.1 to 30 mg/kgof body weight or so, preferably from 1 to 20 mg/kg of body weight orso, in terms of the active ingredient of compound (I), (Ia), (Ib) or(Ic), and this may be administered once or several times a day.

Any ordinary organic and inorganic carrier substances that are generallyused in formulating medicines are usable as the carriers for formulatingthe pharmaceutical compositions of the present invention. For example,employable are ordinary excipients, lubricants, binders, disintegrators,etc. for formulating solid preparations; and solvents, solubilizers,suspending agents, isotonizing agents, buffers, soothing agents, etc.for formulating liquid preparations. If desired, further employable areother additives such as preservatives, antioxidants, colorants,sweeteners, absorbents, wetting agents, etc.

The excipients include, for example, lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light silicic anhydride,etc.

The lubricants include, for example, magnesium stearate, calciumstearate, talc, colloidal silica, etc.

The binders include, for example, crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethyl cellulose sodium, etc.

The disintegrators include, for example, starch, carboxymethylcellulose, carboxymethyl cellulose calcium, croscarmellose sodium,carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.

The solvents include, for example, water for injections, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Thesolubilizers include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

The suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate, etc.; hydrophilic polymers such as polyvinyl alcohol,polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, etc.

The isotonizing agents include, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol, etc.

The buffers include, for example, liquid buffers of phosphates,acetates, carbonates, citrates, etc.

The soothing agents include, for example, benzyl alcohol, etc.

A The preservatives include, for example, parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, etc.

The antioxidants include, for example, sulfites, ascorbic acid, etc.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention will be described in more detail hereinunder, withreference to the following Reference Examples, Examples, FormulationExamples and Experimental Examples, which, however, are to concretelyillustrate some embodiments of the invention and are not intended torestrict the scope of the invention. Various changes and modificationscan be made within the range that does not deviate the scope of theinvention.

“Room temperature” as referred to in the following Reference Examplesand Examples is meant to indicate a temperature falling between 10° C.and 35° C. Unless otherwise specifically indicated, “%” is by weight.The yield indicates mol/mol %.

The meanings of the abbreviations used hereinunder are as follows:

s: singlet

d: doublet

t: triplet

q: quartet

dd: double doublet

ddd: double double doublet

dt: double triplet

br: broad

J: coupling constant

Hz: Hertz

CDCl₃: deuterated chloroform

¹H-NMR: proton nuclear magnetic resonance spectrum

Me: methyl

REFERENCE EXAMPLE 1

1-(4-Methoxyphenyl)-2-(3-pyridyl)ethanone

To a stirred solution of diisopropylamine (33.2 mL) in drytetrahydrofuran (300 mL) cooled at −78° C., was added a solution of 1.6M n-butyllithium in hexane (148 mL) dropwise. After addition, theresulting mixture was stirred for 10 min at the same temperature,followed by the addition of β-picoline (20 g). The resulting mixture wasallowed to warm up to −10-0° C. After an additional 20 min stirring, asolution of ethyl p-anisate (19.4 g) in dry tetrahydrofuran (40 mL) wasadded. After addition the mixture was stirred for another 1 h at ambienttemperature, and water (100 mL) was added to the mixture. The solventwas removed under reduced pressure and the oily product was extractedwith ethyl acetate. The extracts were washed with water, dried, andconcentrated under reduced pressure. The crystalline residue wasrecrystallized from ethyl acetate—isopropyl ether to afford the titlecompound (20.8 g, yield 85%).

mp 71-72° C.

REFERENCE EXAMPLE 2

Using ethyl benzoate, ethyl 3,4-dimethoxybenzoate, ethyl3,4,5-trimethoxybenzoate, ethyl 4-(methoxymethoxy)benzoate, ethyl4-fluorobenzoate, ethyl 4-ethylbenzoate, ethyl3,4-methylenedioxybenzoate, methyl 5-indanecarboxylate, methyl5,6,7,8-tetrahydro-2-naphthoic acid, methyl1,4-benzodioxane-6-carboxylate, and methyl 2-naphthoic acid instead ofusing ethyl p-anisate, the below Reference Example Compounds 2-1 to 2-11were obtained in the same manner as described in the above ReferenceExample 1.

Reference Example Compound 2-1:

1-Phenyl-2-(3-pyridyl)ethanbne

mp 44.5-45.5° C.

Reference Example Compound 2-2:

1-(3,4-Dimethoxyphenyl)-2-(3-pyridyl)ethanone

mp 114-115° C.

Reference Example Compound 2-3:

2-(3-Pyridyl)-1-(3,4,5-trimethoxyphenyl)ethanone

mp 104-105° C.

Reference Example Compound 2-4:

1-(4-Methoxymethoxyphenyl)-2-(3-pyridyl)ethanone

mp 43-44° C.

Reference Example Compound 2-5:

1-(4-Fluorophenyl)-2-(3-pyridyl)ethanone

oil.

Reference Example Compound 2-6:

1-(4-Ethylphenyl)-2-(3-pyridyl)ethanone

mp 80-81° C.

Reference Example Compound 2-7:

1-(3,4-Methylenedioxyphenyl)-2-(3-pyridyl)ethanone

mp 98-99° C.

Reference Example Compound 2-8:

1-(5-Indanyl)-2-(3-pyridyl)ethanone

mp 55-56° C.

Reference Example Compound 2-9:

2-(3-Pyridyl)-1-(5,6,7,8-tetrahydro-2-naphthyl)ethanone

mp 65-66° C.

Reference Example Compound 2-10:

1-(1,4-Benzodioxan-6-yl)-2-(3-pyridyl)ethanone

mp 89-90° C.

Reference Example Compound 2-11:

1-(2-Naphtyl)-2-(3-pyridyl)ethanone

mp 69-70° C.

REFERENCE EXAMPLE 3

Using α-picoline, γ-picoline, and 3,5-lutidine instead of usingβ-picoline, the below Reference Example Compounds 3-1 to 3-5 wereobtained in the same manner as described in the above Reference Example2.

Reference Example Compound 3-1:

1-Phenyl-2-(2-pyridyl)ethanone

mp 59-60° C.

Reference Example Compound 3-2:

1-(4-Methoxyphenyl)-2-(2-pyridyl)ethanone

mp 77-78° C.

Reference Example Compound 3-3:

1-Phenyl-2-(4-pyridyl)ethanone

mp 109-110° C.

Reference Example Compound 3-4:

1-(4-Methoxyphenyl)-2-(4-pyridyl)ethanone

mp 103-104° C.

Reference Example Compound 3-5:

2-(5-Methyl-3-pyridyl)-1-phenylethanone

mp 53-54° C.

REFERENCE EXAMPLE 4

2-Cyano-2-phenyl-1-(3-pyridyl)ethanone

To a solution of ethyl nicotinate (10 g) and phenylacetonitrile (5.1 g)in tert-butyl alcohol (30 mL), was added potassium tert-butoxide (6.4g), and the mixture was stirred at 100° C. for 3 h. After cooling, theresulting mixture was dissolved in water and washed with isopropylether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloricacid and extracted with ethyl acetate. The extracts were washed withwater, dried, and the solvent was evaporated. The crystalline residuewas recrystallized from ethyl acetate-isopropyl ether to obtain thetitle compound (6.0 g, yield 62%).

mp 148-149° C.

REFERENCE EXAMPLE 5

2-Phenyl-1-(3-pyridyl)ethanone

2-Cyano-2-phenyl-1-(3-pyridyl)ethanone (5.0 g) was dissolved in 48%hydrobromic acid (50 mL) and the solution was stirred at 140° C. for 5h. After the mixture was cooled, the mixture was neutralized with anaqueous saturated solution of sodium hydrogen carbonate and the productwas extracted with ethyl acetate. The extracts were washed with water,dried, and the solvent was evaporated. The crystalline residue wasrecrystallized from isopropyl ether to obtain the title compound (3.9 g,yield 88%).

mp 61-62° C.

REFERENCE EXAMPLE 6

2-Bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone Hydrobromide

1-(4-Methoxyphenyl)-2-(3-pyridyl)ethanone (6.85 g) was dissolved inacetic acid (36 mL), bromine (1.7 mL) was added to the solution and theresulting mixture was stirred at 80° C. for 3 h. After the mixture wascooled with ice-water, the crude crystalline mass was collected byfiltration. The crude crystalline was recrystallized from ethanol-ethylether to afford the title compound (10.4 g, yield 89%).

mp 188-195° C.

REFERENCE EXAMPLE 7

Using 1-phenyl-2-(3-pyridyl)ethanone,1-(3,4-dimethoxyphenyl)-2-(3-pyridyl)ethanone,2-(3-pyridyl)-1-(3,4,5-trimethoxyphenyl)ethanone,1-(4-methoxymethoxyphenyl)-2-(3-pyridyl)ethanone,1-(4-fluorophenyl)-2-(3-pyridyl)ethanone,1-phenyl-2-(2-pyridyl)ethanone,1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone,1-phenyl-2-(4-pyridyl)ethanone,1-(4-methoxyphenyl)-2-(4-pyridyl)ethanone,2-(5-methyl-3-pyridyl)-1-phenylethanone,1-(4-ethylphenyl)-2-(3-pyridyl)ethanone,1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone, 1-(5-indanyl)-2-(3-pyridyl)ethanone,2-(3-pyridyl)-1-(5,6,7,8-tetrahydro-2-naphthyl)ethanone,1-(1,4-benzodioxan-6-yl)-2-(3-pyridyl)ethanone,1-(2-naphthyl)-2-(3-pyridyl)ethanone,1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone and2-phenyl-1-(3-pyridyl)ethanone instead of using1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone, the below Reference ExampleCompounds 7-1 to 7-18 were obtained in the same manner as described inthe above Reference Example 6.

Reference Example Compound 7-1:

2-Bromo-1-phenyl-2-(3-pyridyl)ethanone Hydrobromide

mp 208-215° C.

Reference Example Compound 7-2:

2-Bromo-1-(3,4-dimethoxyphenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 191-193° C.

Reference Example Compound 7-3:

2-Bromo-2-(3-pyridyl)-1-(3,4,5-trimethoxyphenyl)ethanone Hydrobromide

mp 184-186° C.

Reference Example Compound 7-4:

2-Bromo-1-(4-hydroxyphenyl)-2-(3-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used in the next reaction.

Reference Example Compound 7-5:

2-Bromo-1-(4-fluorophenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 189-191° C.

Reference Example Compound 7-6:

2-Bromo-1-phenyl-2-(2-pyridyl)ethanone Hydrobromide

mp 180-181° C.

Reference Example Compound 7-7:

2-Bromo-1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone Hydrobromide

mp 170-171° C.

Reference Example Compound 7-8:

2-Bromo-1-phenyl-2-(4-pyridyl)ethanone Hydrobromide

mp 230-232° C.

Reference Example Compound 7-9:

2-Bromo-1-(4-methoxyphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 207-209° C.

Reference Example Compound 7-10:

2-Bromo-2-(5-methyl-3-pyridyl)-1-phenylethanone Hydrobromide

mp 189-193° C.

Reference Example Compound 7-11:

2-Bromo-1-(4-ethylphenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 145-146° C.

Reference Example Compound 7-12:

2-Bromo-1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 174-175° C.

Reference Example Compound 7-13:

2-Bromo-1-(5-indanyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 177-178° C.

Reference Example Compound 7-14:

2-Bromo-2-(3-pyridyl)-1-(5,6,7,8-tetrahydro-2-naphthyl)ethanoneHydrobromide

mp 160-162° C.

Reference Example Compound 7-15:

1-(1,4-Benzodioxan-6-yl)-2-bromo-2-(3-pyridyl)ethanone Hydrobromide

oil.

Reference Example Compound 7-16:

2-Bromo-1-(2-naphthyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 197-199° C.

Reference Example Compound 7-17:

2-Bromo-1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone Hydrobromide

mp 170-171° C.

Reference Example Compound 7-18:

2-Bromo-2-phenyl-1-(3-pyridyl)ethanone Hydrobromide

mp 213-218° C.

REFERENCE EXAMPLE 8

[4-(4-Methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine

To a suspension of thiourea (516 mg) in acetonitrile (40 mL), was added2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide (2.5 g),and then triethylamine (0.95 mL) was added slowly dropwise to themixture with stirring. After addition, the mixture was stirred at refluxfor 3 h. After cooling, the crude crystalline was collected byfiltration. The crystalline was washed with an aqueous saturatedsolution of sodium hydrogen carbonate, water, ethanol, and ethyl ether,in that order, and dried. The obtained crude crystalline wasrecrystallized from tetrahydrofuran to give the title compound (1.5 g,yield 90%).

mp 265-266° C.

REFERENCE EXAMPLE 9

N-Methyl[4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine

To a suspension of N-methylthiourea (242 mg) in acetonitrile (18 mL),was added 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone hydrobromide(1.0 g) and then triethylamine (0.4 mL) was added slowly dropwise to themixture. After addition, the resulting mixture was stirred at reflux for3 h, and the solvent was evaporated. An aqueous saturated solution ofsodium hydrogen carbonate was added to the residue and extracted withethyl acetate. The extracts were washed with water, dried, and thesolvent was evaporated. The crystalline residue was recrystallized fromethyl acetate-isopropyl ether to afford the title compound (650 mg,yield 85%).

mp 158-159° C.

REFERENCE EXAMPLE 10

N-[4-(4-Methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide

Using [(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine asstarting material, the title compound was obtained in the same manner asdescribed in below Example 3. Yield 82%.

mp 208-210° C.

REFERENCE EXAMPLE 11

2-(4-Acetylpiperazin-1-yl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole

To a solution of 1-piperazinecarbothioamide (387 mg) in acetonitrile (15mL), was added 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanonehydrobromide (1.0 g), and then triethylamine (0.4 mL) was added slowlydropwise to the resulting mixture. After addition the mixture wasstirred at reflux for3 h and the solvent was evaporated. An aqueoussaturated solution of sodium hydrogen carbonate was added to the residueand extracted with ethyl acetate. The extracts were washed with water,dried and the solvent was evaporated. The residue was dissolved inpyridine (2 mL) and acetyl chloride (0.3 mL) was added to the solutionunder ice cooling. The resulting mixture was stood at room temperaturefor 1 h. The reaction mixture was poured into ice-water and the productwas extracted with ethyl acetate. The extracts were washed with water,dried, and the solvent was evaporated. The residue was purified usingsilica-gel column chromatography (ethyl acetate-methanol, 9:1) to givethe title compound (300 mg, yield 28%).

oil.

REFERENCE EXAMPLE 12

[4-(4-Methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]amine Hydrochloride

[4-(4-Methoxyphenyl)-5-(3-pyridyl)-I,3-thiazol-2-yl]amine (200 mg) wasdissolved in 1% methanol solution of hydrogen chloride (3.2 mL), and thesolvent was evaporated. The crude crystalline was recrystallized frommethanol-ethyl acetate to give the title compound (180 mg, yield 80%).

mp 145-150° C.

The chemical structures of the compounds obtained in the ReferenceExamples 8 to 12 are shown in Table 1.

TABLE 1

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive 8 —NH₂

9 —NHMe

10 —NHCOMe

11

12 —NH₂

HCl

REFERENCE EXAMPLE 13

The following Reference Example Compounds13-1 to 13-106 shown in Tables2 to 7 were obtained in the same manner as described in the aboveReferences 8 to 12, JP-A-61-10580 and U.S. Pat. No. 4,612,321.

TABLE 2

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 13-1 —NHMe

168-169 13-2 —NH₂

253-254 13-3 —NH₂

240-241 13-4 —NH₂

168-169 13-5 —NHMe

157-158 13-6 —NHMe

205-206 13-7 —NH₂

266-268 13-8 —NHCOCH₂COOCH₂Me

201-202 13-9 —NHCOCH₂COOMe

185-186 13-10 —NH₂

236-237 13-11 —NHMe

215-216 13-12 —NHMe

214-215 13-13 —NH₂

217-218 13-14 —NH₂

282-284 13-15 —NH₂

248-250 13-16 —NHMe

177-178 13-17

130-131 13-18

134-135

TABLE 3

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 13-19 —CH₂Me

84-84.5 13-20 —CH₂Me

59-60 13-21 —CH₂Me

174-175 13-22 —Me

113-114 13-23 —CH₂Me

83-84 13-24

135-136 13-25

104-105 13-26

96-98 13-27

195-196 13-28

211-213 13-29

280-282 13-30

100-101 13-31

92-93 13-32

111-112 13-33

264-265 13-34

245-246 13-35

247-248

TABLE 4

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 13-36 —Me

208-209 13-37

255-256 13-38

225-226 13-39 —(CH₂)₃COOH

143-144 13-40 —(CH₂)₃COOH

163-164 13-41 —(CH₂)₃COOH

134-135 13-42 —(CH₂)₃COOH

112-113 13-43 —(CH₂)₄OH

51-52 13-44 —NHCH₂Me

154-155 13-45 —NHMe

187-188 13-46 —NHMe

124-125 13-47 —NHMe

191-192 13-48 —N(CH₂Me)₂

oil 13-49 —NME₂

oil 13-50 —CH₂Me

oil 13-51 —CH₂Me

oil 13-52 —(CH₂)₃Me

oil 13-53 —CH₂Me

oil

TABLE 5

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 13-54

104-105 13-55 —CH₂COOH

oil 13-56 —(CH₂)₃COOMe

oil 13-57 —(CH₂)₅COOH

oil 13-58 —(CH₂)₅COOH

oil 13-59 —(CH₂)₄OH

oil 13-60 —(CH₂)₆OH

oil 13-61 —(CH₂)₂Me

oil 13-62 —CHMe₂

oil 13-63 —NMe₂

76-77 13-64 —N(CH₂Me)₂

97-98 13-65 —NHMe

234-235 13-66 —NMe₂

144-145 13-67 —NHMe

146-147 13-68 —NHMe

153-154 13-69 —NHMe

205-206 13-70 —NHMe

224-225 13-71 —NHMe

206-207

TABLE 6

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive mp/° C. 13-72 —NHMe

191-192 13-73 —NHMe

168-169 13-74 —NHMe

172-173 13-75

126-127 13-76

222-223 13-77

132-133 13-78

90-91 13-79

148-149 13-80

180-181 13-81

240-241 13-82

258-259 13-83 —NMe₂

85-86 13-84 —N(CH₂Me)₂

56-57 13-85 —CH₂NH₂

oil 13-86 —CH₂NHMe

oil 13-87 —NHCOMe

HCl 214-217 13-88 —NHCOMe

228-231 13-89 —NHCOMe

HCl 275-278 13-90 —NHCOCH₂Me

HCl 248-251

TABLE 7

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 13-91 —NHCOCH₂Me

196-199 13-92 —NHCOCHMe₂

213-216 13-93 —NH₂

212-215 13-94 —NHCOMe

230-233 13-95 —NH₂

186-189 13-96 —NHCOMe

230-234 13-97

275-278 13-98 —NHCOMe

287-292 13-99 —NMeCOMe

169-172 13-100 —NHCOMe

222-224 13-101 —NHCOMe

175-178 13-102 —N═CHNMe₂

118-120

REFERENCE EXAMPLE 14

N-(4-Chlorobenzoyl)propyleneimine

A solution of propyleneimine (12.3 mL) in tetrahydrofuran (160 mL) wasadded to an 1N aqueous sodium hydroxide solution. To the mixture wasadded dropwise 4-chlorobenzoyl chloride (25 g) at 0° C. After addition,the mixture was stirred for additional 30 min. The reaction mixture wasextracted with ethyl acetate. The extract was dried, concentrated underreduced pressure to afford the title compound (24.9 g, yield 89%).

oil. ¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.15 (1H, d, J=2.9 Hz),2.51-2.66 (2H, m), 7.39-7.47 (2H, m), 7.93-8.01 (2H, m).

REFERENCE EXAMPLE 15

Using 3-chlorobenzoyl chloride, 2-chlorobenzoyl chloride,2-methylbenzoyl chloride, 3-methylbenzoyl chloride, 4-methylbenzoylchloride, 2-methoxybenzoyl chloride, 3-methoxybenzoyl chloride,4-ethylbenzoyl chloride, 4-(1-methylethyl)benzoyl chloride,4-(1,1-dimethylethyl)benzoyl chloride, 4-propylbenzoyl chloride,4-butylbenzbyl chloride, 4-hexylbenzoyl chloride,4-trifluoromethoxybenzoyl chloride, 4-trifluoromethylbenzoyl chloride,3,4-dimethoxybenzoyl chloride, 3,4-dimethylbenzoyl chloride,3,5-dimethylbenzoyl chloride, 3,4-methylenedioxybenzoyl chloride and2-naphthoyl chloride instead of using 4-chlorobenzoyl chloride, thebelow Reference Example Compounds 15-1 to 15-20 were obtained in thesame manner as described in the above Reference Example 14.

Reference Example Compound 15-1:

N-(3-Chlorobenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.1 Hz), 2.17 (1H, d, J=3.3 Hz),2.53-2.68 (2H, m), 7.40 (1H, dd, J=8.1, 7.7 Hz), 7.53 (1H, ddd, J=8.1,2.2, 1.5 Hz), 7.90 (1H, dt, J=7.7, 1.5 Hz), 8.00 (1H, dd, J=2.2, 1.5Hz).

Reference Example Compound 15-2:

N-(2-Chlorobenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=5.1 Hz), 2.12 (1H, d, J=3.3 Hz),2.53 (1H, d, J=5.5 Hz), 2.56-2.68 (1H, m), 7.28-7.48 (3H, m), 7.75-7.81(1H, m).

Reference Example Compound 15-3:

N-(2-Methylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=5.5 Hz), 2.08 (1H, d, J=3.3 Hz),2.43-2.57 (5H, m), 7.20-7.31 (2H, m), 7.33-7.43 (1H, m), 7.89 (1H, d,J=7.7 Hz).

Reference Example Compound 15-4:

N-(3-Methylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.14 (1H, d, J=3.3 Hz),2.41 (3H, s), 2.51-2.66 (2H, m), 7.32-7.39 (2H, m), 7.79-7.87 (2H, m).

Reference Example Compound 15-5:

N-(4-Methylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.12 (1H, d, J=2.9 Hz),2.42 (3H, s), 2.50-2.62 (2H, m), 7.25 (2H, d, J=8.1 Hz), 7.92 (2H, d,J=8.1 Hz).

Reference Example Compound 15-δ:

N-(2-Methoxybenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.30 (3H, d, J=5.5 Hz), 2.10 (1H, d, J=3.3 Hz),2.50 (1H, d, J=5.9 Hz), 2.53-2.65 (1H, m), 3.90 (3H, s), 6.95-7.05 (2H,m), 7.41-7.52 (1H, m) 7.81-7.88 (1H, m).

Reference Example Compound 15-7:

N-(3-Methoxybenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.9 Hz), 2.14 (1H, d, J=2.9 Hz),2.52-2.65 (2H, m), 3.86 (3H, s), 7.10 (1H, ddd, J=8.4, 2.6, 1.1 Hz),7.37 (1H, dd, J=8.4, 7.3 Hz), 7.55 (1H, dd, J=2.6, 1.5 Hz), 7.63 (1H,ddd, J=7.3, 1.5, 1.1 Hz).

Reference Example Compound 15-8:

N-(4-Ethylbenzoyl)propyleneimine

oil. ¹H-NMR. (CDCl₃) δ: 1.27 (3H, t, J=7.6 Hz), 1.39 (3H, d, J=5.5 Hz),2.13 (1H, d, J=3.3 Hz), 2.50-2.61 (2H, m), 2.71 (2H, q, J=7.6 Hz), 7.28(2H, d, J=7.7 Hz), 7.95 (2H, d, J=7.7 Hz).

Reference Example Compound 15-9:

N-[4-(1-Methylethyl)benzoyl]propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=7.0 Hz), 1.40 (3H, d, J=5.5 Hz),2.13 (1H, d, J=3.3 Hz), 2.50-2.64 (2H, m), 2.90-3.05 (1H, m), 7.31 (2H,d, J=8.2 Hz), 7.96 (2H, d, J=8.2 Hz).

Reference Example Compound 15-10:

N-[4-(1,1-Dimethylethyl)benzoyl]propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.41 (3H, d, J=5.5 Hz), 2.12 (1H,d, J=2.9 Hz), 2.51-2.64 (2H, m), 7.47 (2H, d, J=8.8 Hz), 7.96 (2H, d,J=8.8 Hz).

Reference Example Compound 15-11:

N-(4-Propylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 0.96 (3H, t, J=7.3 Hz), 1.39 (3H, d, J=5.5 Hz),1.57-1.75 (2H, m), 2.12 (1H, d, J=3.3 Hz), 2.50-2.59 (2H, m), 2.65 (2H,t, J=7.7 Hz), 7.26 (2H, d, J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz).

Reference Example Compound 15-12:

N-(4-Butylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.1 Hz), 1.26-1.47 (5H, m),1.54-1.73 (2H, m), 2.12 (1H, d, J=2.9 Hz), 2.51-2.62 (2H, m), 2.67 (2H,t, J=7.7 Hz), 7.26 (2H, d, J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz).

Reference Example Compound 15-13:

N-(4-Hexylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 0.89 (3H, t, J=6.6 Hz), 1.24-1.38 (6H, m), 1.39(3H, d, J=5.5 Hz), 1.56-1.68 (2H, m), 2.12 (1H, d, J=3.3 Hz), 2.51-2.61(2H, m), 2.66 (2H, t, J=7.7 Hz), 7.26 (2H, d, J=8.1 Hz), 7.94 (2H, d,J=8.1 Hz).

Reference Example Compound 15-14:

N-(4-Trifluoromethoxybenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.5 Hz), 2.16 (1H, d, J=3.3 Hz),2.53-2.68 (2H, m), 7.29 (2H, d, J=9.0 Hz), 8.08 (2H, d, J=9.0 Hz).

Reference Example Compound 15-15:

N-(4-Trifluoromethylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=5.5 Hz), 2.19 (1H, d, J=3.7 Hz),2.54-2.70 (2H, m), 7.73 (2H, d, J=8.0 Hz), 8.13 (2H, d, J=8.0 Hz).

Reference Example Compound 15-16:

N-(3,4-Dimethoxybenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.41 (3H, d, J=5.5 Hz), 2.12 (1H, d, J=3.3 Hz),2.51-2.63 (2H, m), 3.94 (3H, s), 3.95 (3H, s), 6.92 (1H, d, J=8.5 Hz),7.56 (1H, d, J=2.2 Hz), 7.69 (1H, dd, J=8.5, 2.2 Hz).

Reference Example Compound 15-17:

N-(3,4-Dimethylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.12 (1H, d, J=3.3 Hz),2.32 (6H, s), 2.49-2.61 (2H, m), 7.21 (1H, d, J=,7.7 Hz), 7.77 (1H, dd,J=7.7, 1.8 Hz), 7.80 (1H, d, J=1.8 Hz).

Reference Example Compound 15-18:

N-(3,5-Dimethylbenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=5.5 Hz), 2.13 (1H, d, J=3.7 Hz),2.37 (6H, s), 2.47-2.62 (2H, m), 7.19 (1H, s), 7.64 (2H, s).

Reference Example Compound 15-19:

N-(3,4-Methylenedioxybenzoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.38 (3H, d, J=4.9 Hz), 2.11 (1H, d, J=3.1 Hz),2.48-2.64 (2H, m), 6.05 (2H, s), 6.86 (1H, d, J=8.2 Hz), 7.48 (1H, d,J=1.7 Hz), 7.65 (1H, dd, J=8.2, 1.7 Hz).

Reference Example Compound 15-20:

N-(2-Naphthoyl)propyleneimine

oil. ¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=5.5 Hz), 2.22 (1H, d, J=3.3 Hz),2.57-2.84 (2H, m), 7.50-7.65 (2H, m), 7.85-8.00 (3H, m), 8.06 (1H, dd,J=8.6, 1.5 Hz), 8.59 (1H, s)

REFERENCE EXAMPLE 16

1-(2-Chlorophenyl)-2-(4-pyridyl)ethanone

To a stirred solution of diisopropylamine (15.4 mL) in drytetrahydrofuran (100 mL) cooled at −50° C., was added a solution of 1.6M n-butyllithium in hexane (69 mL) dropwise. After addition, theresulting mixture was stirred for 10 min at the same temperature,followed by the addition of a solution of γ-picoline (20 g) in drytetrahydrofuran (10 mL) at −30° C. After an additional 1 h stirring, asolution of N-(2-chlorobenzoyl)propyleneimine (20 g) in drytetrahydrofuran (10 mL) was added dropwise to the resulting mixture at−10° C. After addition the mixture was stirred for another 2 h atambient temperature. Water (100 mL) was added to the mixture andextracted with ethyl acetate. The extract was washed with water, dried,and concentrated under reduced pressure. The residue was purified usingsilica-gel column chromatography (hexane-ethyl acetate, 1:1) to give thetitle compound (16.4 g, yield 71%).

oil. ¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 7.20 (2H, d, J=6.2 Hz,), 7.28-7.39(1H, m), 7.41-7.48 (3H, m), 8.56 (2H, d, J=6.2 Hz).

REFERENCE EXAMPLE 17

Using N-(3-chlorobenzoyl)propyleneimine,N-(4-chlorobenzoyl)propyleneimine, N-(2-methylbenzoyl)propyleneimine,N-(3-methylbenzoyl)propyleneimine, N-(4-methylbenzoyl)propyleneimine,N-(2-methoxybenzoyl)propyleneimine, N-(3-methoxybenzoyl)propyleneimine,N-(4-ethylbenzoyl)propyleneimine,N-(4-(1-methylethyl)benzoyl]propyleneimine,N-[4-(1,1-dimethylethyl)benzoyl]propyleneimine,N-4-(propylbenzoyl)propyleneimine, N-(4-butylbenzoyl)propyleneimine,N-(4-hexylbenzoyl)propyleneimine,N-(4-trifluoromethoxybenzoyl)propyleneimine,N-(4-trifluoromethylbenzoyl)propyleneimine,N-(3,4-dimethoxybenzoyl)propyleneimine,N-(3,4-dimethylbenzoyl)propyleneimine,N-(3,5-dimethylbenzoyl)propyleneimine,N-(3,4-methylenedioxybenzoyl)propyleneimine andN-(2-naphthoyl)propyleneimine instead of usingN-(2-chlorobenzoyl)propyleneimine, the below Reference Example Compounds17-1 to 17-20 were obtained in the same manner as described in the aboveReference Example 16.

Reference Example Compound 17-1:

1-(3-Chlorophenyl)-2-(4-pyridyl)ethanone

mp 79-80° C.

Reference Example Compound 17-2:

1-(4-Chlorophenyl)-2-(4-pyridyl)ethanone

mp 93-94° C.

Reference Example Compound 17-3:

1-(2-Methylphenyl)-2-(4-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 4.23 (2H, s), 7.19 (2H, d, J=6.2Hz), 7.24-7.47 (3H, m), 7.73 (1H, d, J=7.7 Hz), 8.56 (2H, d, J=6.2 Hz).

Reference Example Compound 17-4:

1-(3-Methylphenyl)-2-(4-pyridyl)ethanone

mp 115-116° C.

Reference Example Compound 17-5:

1-(4-Methylphenyl)-2-(4-pyridyl)ethanone

mp 110-111° C.

Reference Example Compound 17-6:

1(2-Methoxyphenyl)-2-(4-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 4.30 (2H, s), 6.95-7.07 (2H, m),7.17 (2H, d, J=5.9 Hz), 7.50 (1H, ddd, J=8.4, 7.3, 1.8 Hz), 7.73 (1H,dd, J=7.7, 1.8 Hz), 8.53(2H, d, J=5.9 Hz).

Reference Example Compound 17-7:

1-(3-Methoxyphenyl)-2-(4-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 4.28 (2H, s), 7.14 (1H, ddd, J=8.1,2.6, 1.1 Hz), 7.20 (2H, d, J=6.2 Hz) 7.36 (1H, dd, J=8.1, 7.7 Hz), 7.51(1H, dd, J=2.6, 1.5 Hz), 7.58 (1H, ddd, J=7.7, 1.5, 1.1 Hz) 8.57 (2H, d,J=6.2 Hz).

Reference Example Compound 17-8:

1-(4-Ethylphenyl)-2-(4-pyridyl)ethanone

mp 87-89° C.

Reference Example Compound 17-9:

1-[4-(1-Methylethyl)phenyl]-2-(4-pyridyl)ethanone

mp 86-88° C.

Reference Example Compound 17-10:

1-[4-(1,1-Dimethylethyl)phenyl]-2-(4-pyridyl)ethanone

mp 75-76° C.

Reference Example Compound 17-11:

1-(4-Propylphenyl)-2-(4-pyridyl)ethanone

mp 71-72° C.

Reference Example Compound 17-12:

1-(4-Butylphenyl)-2-(4-pyridyl)ethanone

mp 41-43° C.

Reference Example Compound 17-13:

1-(4-Hexylphenyl)-2-(4-pyridyl)ethanone

mp 57-58° C.

Reference Example Compound 17-14:

2-(4-Pyridyl)-1-(4-trifluoromethoxyphenyl)ethanone

mp 65-66° C.

Reference Example Compound 17-15:

2-(4-Pyridyl)-1-(4-trifluoromethylphenyl)ethanone

mp 94-95° C.

Reference Example Compound 17-16:

1-(3,4-Dimethoxyphenyl)-2-(4-pyridyl)ethanone

mp 110-111° C.

Reference Example Compound 17-17:

1-(3,4-Dimethylphenyl)-2-(4-pyridyl)ethanone

mp 81-83° C.

Reference Example Compound 17-18:

1-(3,5-Dimethylphenyl)-2-(4-pyridyl)ethanone

mp 90-91° C.

Reference Example Compound 17-19:

1-(3,4-Methylenedioxyphenyl)-2-(4-pyridyl)ethanone

mp 126-127° C.

Reference Example Compound 17-20:

1-(2-Naphthyl)-2-(4-pyridyl)ethanone

mp 114-115° C.

REFERENCE EXAMPLE 18

Using α-picoline instead of using γ-picoline, the below

Reference Example Compounds 18-1 to 18-9 were obtained in the samemanner as described in the above Reference Example 17.

Reference Example Compound 18-1:

1-(2-Chlorophenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 7.18-7.49 (5H, m), 7.59-7.67(1H,m), 8.47-8.56 (2H, m).

Reference Example Compound 18-2:

1-(3-Chlorophenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 4.29 (2H, s), 7.25-7.34 (1H, m), 7.44 (1H, t,J=7.7 Hz), 7.54-7.63 (2H, m), 7.90 (1H, dt, J=7.7, 1.5 Hz), 8.00 (1H,dd, J=1.8, 1.5 Hz), 8.49-8.57 (2H, m).

Reference Example Compound 18-3:

1-(4-Chlorophenyl)-2-(3-pyridyl)ethanone

¹H-NMR (CDCl₃) δ: 4.27 (2H, s), 7.24-7.31 (1H, m), 7.47 (2H, d, J=8.8Hz), 7.55-7.63 (1H, m), 7.96 (2H, d, J=8.8 Hz), 8.46-8.53 (2H, m).

Reference Example Compound 18-4:

1-(2-Methylphenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 4.23 (2H, s), 7.18-7.47 (5H, m),7.73 (1H, d, J=7.7 Hz), 8.47-8.56 (2H, m).

Reference Example Compound 18-5:

1-(3-Methylphenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 4.29 (2H, s), 7.17-7.36 (1H, m),7.36-7.46 (2H, m), 7.58-7.65 (1H, m), 7.78-7.86 (2H, m), 8.50-8.56 (2H,m).

Reference Example Compound 18-6:

1-(4-Methylphenyl)-2-(3-pyridyl)ethanone

mp 72-74° C.

Reference Example Compound 18-7:

1-(3-Methoxyphenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 4.29 (2H, s), 7.14 (1H, ddd, J=8.1,2.6, 1.8 Hz), 7.28 (1H, dd, J=7.3, 4.8 Hz), 7.40 (1H, dd, J=8.1, 7.7Hz), 7.53 (1H, dd, J=2.6, 1.8 Hz), 7.58-7.65 (2H, m), 8.50-8.55 (2H, m).

Reference Example Compound 18-8:

1-[4-(1,1-Dimethylethyl)phenyl]-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 1.34 (9H, s), 4.28 (2H, s), 7.22-7.31 (1H, m),7.50 (2H, d, J=8.4 Hz), 7.56-7.65 (1H, m), F 7.96 (2H, d, J=8.4 Hz),8.48-8.55 (2H, m).

Reference Example Compound 18-9:

1-(3,5-Dimethylphenyl)-2-(3-pyridyl)ethanone

oil. ¹H-NMR (CDCl₃) δ: 2.38 (6H, s), 4.27 (2H, s), 7.24-7.30 (2H, m),7.58-7.63 (3H, m), 8.50-8.52 (2H, m).

REFERENCE EXAMPLE 19

Using ethyl 4-dimethylaminobenzoate instead of using ethyl p-anisate,the below Reference Example Compound 19 was obtained in the same manneras described in the above Reference Example 1.

Reference Example Compound 19:

1-(4-Dimethylaminophenyl)-2-(4-pyridyl)ethanone

mp 189-192° C.

REFERENCE EXAMPLE 20

2-[4-(1,1-Dimethylethyl)phenyl]-1-(4-pyridyl)ethanone

To a solution of ethyl isonicotinate (12 g) and4-(1,1-Dimethylethyl)phenylacetonitrile (9.1 g) in tert-butyl alcohol(36 mL), was added potassium tert-butoxide (7.3 g), and the mixture wasstirred at 100° C. for 3 h. After cooling, the resulting mixture wasdissolved in water and washed with isopropyl ether. The aqueous phasewas adjusted to pH 7.0 with 2 N hydrochloric acid and extracted withethyl acetate. The extract was washed with water, dried, And the solventwas evaporated. The crystalline residue was recrystallized from ethylacetate-isopropyl ether to obtain2-cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.09 g,yield 35%).

2-Cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.0 g)obtained above was dissolved in 48% hydrobromic acid (50 mL) and thesolution was stirred at 140° C. for 5 h. After the mixture was cooled,the mixture was neutralized with an aqueous saturated solution of sodiumhydrogen carbonate and the product was extracted with ethyl acetate. Theextract was washed with water, dried, and the solvent was evaporated.The residue was purified using silica-gel column chromatography(hexane-ethyl acetate, 1:1) to obtain the title compound (3.1 g, yield68%).

oil ¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 4.25 (2H, s), 7.18 (2H, d, J=8.4Hz), 7.36 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=6.2 Hz), 8.81 (2H, d, J=6.2Hz).

REFERENCE EXAMPLE 21

2-(3,5-Dimethylphenyl)-1-(4-pyridyl)ethanone

Using 3,5-dimethylphenylacetonitrile instead of using4-(1,1-Dimethylethyl)phenylacetonitrile, the title compound was obtainedin the same manner as described in the above Reference Example 20.

mp 96-97C.

REFERENCE EXAMPLE 22

Using 1-(2-chlorophenyl)-2-(3-pyridyl)ethanone,1-(3-chlorophenyl)-2-(3-pyridyl)ethanone,1-(4-chlorophenyl)-2-(3-pyridyl)ethanone,1-(2-methylphenyl)-2-(3-pyridyl)ethanone,1-(3-methylphenyl)-2-(3-pyridyl)ethanone,1-(4-methylphenyl)-2-(3-pyridyl)ethanone,1-(3-methoxyphenyl)-2-(3-pyridyl)ethanone,1-[4-(1,1-dimethylethyl)phenyl]-2-(3-pyridyl)ethanone,1-(3,5-dimethylphenyl)-2-(3-pyridyl)ethanone,1-(2-chlorophenyl)-2-(4-pyridyl)ethanone,1-(3-chlorophenyl)-2-(4-pyridyl)ethanone,1-(4-chlorophenyl)-2-(4-pyridyl)ethanone,1-(2-methylphenyl)-2-(4-pyridyl)ethanone,1-(3-methylphenyl)-2-(4-pyridyl)ethanone,1-(4-methylphenyl)-2-(4-pyridyl)ethanone,1-(2-methoxyphenyl)-2-(4-pyridyl)ethanone,1-(3-methoxyphenyl)-2-(4-pyridyl)ethanone,1-(4-ethylphenyl)-2-(4-pyridyl)ethanone,1-[4-(1-methylethyl)phenyl]-2-(4-pyridyl)ethanone,1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone,1-(4-propylphenyl)-2-(4-pyridyl)ethanone,1-(4-butylphenyl)-2-(4-pyridyl)ethanone,1-(4-hexylphenyl)-2-(4-pyridyl)ethanone,2-(4-pyridyl)-1-(4-trifluoromethoxyphenyl)ethanone,2-(4-pyridyl)-1-(4-trifluoromethylphenyl)ethanone,1-(4-dimethylaminophenyl)-2-(4-pyridyl)ethanone hydrobromide,1-(3,4-dimethoxyphenyl)-2-(4-pyridyl)ethanone,1-(3,4-dimethylphenyl)-2-(4-pyridyl)ethanone,1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone,1-(3,4-methylenedioxyphenyl)-2-(4-pyridyl)ethanone,1-(2-naphthyl)-2-(4-pyridyl)ethanone,2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone and2-(3,5-dimethylphenyl)-1-(4-pyridyl)ethanone instead of using1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone, the below Reference ExampleCompounds 22-1 to 22-33 were obtained in the same manner as described inthe above Reference Example 6.

Reference Example Compound 22-1:

2-Bromo-1-(2-chlorophenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 88-90° C.

Reference Example Compound 22-2:

2-Bromo-1-(3-chlorophenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 164-166° C.

Reference Example Compound 22-3:

2-Bromo-1-(4-chlorophenyl)-2-(3-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used in the next reaction.

Reference Example Compound 22-4:

2-Bromo-1-(2-methylphenyl)-2-(3-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used in the next reaction.

Reference Example Compound 22-5:

2-Bromo-1-(3-methylphenyl)-2-(3-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used in the next reaction.

Reference Example Compound 22-6:

2-Bromo-1-(4-methylphenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 96-98° C.

Reference Example Compound 22-7:

2-Bromo-1-(3-methoxyphenyl)-2-(3-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used to next reaction.

Reference Example Compound 22-8:

2-Bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(3-pyridyl)ethanoneHydrobromide

mp 190-194° C.

Reference Example Compound 22-9:

2-Bromo-1-(3,5-dimethylphenyl)-2-(3-pyridyl)ethanone Hydrobromide

mp 195-197° C.

Reference Example Compound 22-10:

2-Bromo-1-(2-chlorophenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 157-159° C.

Reference Example Compound 22-11:

2-Bromo-1-(3-chlorophenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 178-181° C.

Reference Example Compound 22-12:

2-Bromo-1-(4-chlorophenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 189-193° C.

Reference Example Compound 22-13:

2-Bromo-1-(2-methylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 183-186° C.

Reference Example Compound 22-14:

2-Bromo-1-(3-methylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used to next reaction.

Reference Example Compound 22-15:

2-Bromo-1-(4-methylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 111-113° C.

Reference Example Compound 22-16:

2-Bromo-1-(2-methoxyphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 168-171° C.

Reference Example Compound 22-17:

2-Bromo-1-(3-methoxyphenyl)-2-(4-pyridyl)ethanone Hydrobromide

The crude mixture without purification was used t next reaction.

Reference Example Compound 22-18:

2-Bromo-1-(4-ethylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 170-173° C.

Reference Example Compound 22-19:

2-Bromo-1-[4-(1-methylethyl)phenyl]-2-(4-pyridyl)ethanone Hydrobromide

mp 185-188° C.

Reference Example Compound 22-20:

2-Bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanoneHydrobromide

mp 209-212° C.

Reference Example Compound 22-21:

2-Bromo-1-(4-propylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 167-170° C.

Reference Example Compound 22-22:

2-Bromo-1-(4-butylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 158-161° C.

Reference Example Compound 22-23:

2-Bromo-1-(4-hexylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 153-155° C.

Reference Example Compound 22-24:

2-Bromo-2-(4-pyridyl)-1-(4-trifluoromethoxyphenyl)ethanone Hydrobromide

The crude mixture without purification was used to next reaction.

Reference Example Compound 22-25:

2-Bromo-2-(4-pyridyl)-1-(4-trifluoromethylphenyl)ethanone Hydrobromide

mp 190-194° C.

Reference Example Compound 22-26:

2-Bromo-1-(4-dimethylaminophenyl)-2-(4-pyridyl)ethanone Dihydrobromide

mp 163-167° C.

Reference Example Compound 22-27:

2-Bromo-1-(3,4-dimethoxyphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 174-175° C.

Reference Example Compound 22-28:

2-Bromo-1-(3,4-dimethylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 196-199° C.

Reference Example Compound 22-29:

2-Bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 216-219° C.

Reference Example Compound 22-30:

2-Bromo-1-(3,4-methylenedioxyphenyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 211-214° C.

Reference Example Compound 22-31:

2-Bromo-1-(2-naphthyl)-2-(4-pyridyl)ethanone Hydrobromide

mp 149-152° C.

Reference Example Compound 22-32:

2-Bromo-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanoneHydrobromide

The crude mixture without purification was used in the next reaction.

Reference Example Compound 22-33:

2-Bromo-2-(3,5-dimethylphenyl)-1-(4-pyridyl)ethanone Hydrobromide

mp 186-188° C.

REFERENCE EXAMPLE 23

The following Reference Example Compounds 23-1 to 23-222 shown in Tables8 to 21 were obtained in the same manner as described in the aboveReferences 5 to 9, JP-A-61-10580 and U.S. Pat. No. 4,612,321.

TABLE 8

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive mp/° C. 23-1

HCl 260 23-2

HCl 244-246 23-3

HCl 255-256 23-4

HCl 275 23-5

233 23-6 —NHCOMe

218-220 23-7 —NHCOMe

218-220 23-8

2HCl 145-148 23-9

238 23-10

228-230 23-11

215-217 23-12 —NHCO(CH₂)₂Me

198-200 23-13 —NHCO(CH₂)₃Me

205-206 23-14 —NHCO(CH₂)₄Me

175-177 23-15 —NHCOCMe₃

219-220 23-16

HCl 268-270 23-17

HCl 243-246

TABLE 9

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive mp/° C. 23-18

HCl 237-239 23-19

HCl 220-223 23-20

184-185 23-21

214-216 23-22 —NHCO(CH₂)₂Me

197-198 23-23 —NHCO(CH₂)₃Me

188-190 23-24 —NHCO(CH₂)₄Me

167-169 23-25 —NHCOCMe₃

245-246 23-26

237-238 23-27

240 23-28

240 23-29

233-234 23-30

214-216 23-31 —NHCOCMe₃

206-208 23-32

247 23-33 —NHCO(CH₂)₂Me

212-214 23-34 —NHCO(CH₂)₃Me

232-234 23-35 —NHCO(CH₂)₄Me

245-246

TABLE 10

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-36

219-220 23-37 —NHCOCH₂Me

254-256 23-38

255-257 23-39 —NH₂

278-280 23-40 —NHCOMe

266-268 23-41 —NHCOCH₂Me

241-242 23-42 —NH₂

286-288 23-43 —NHCOMe

260-261 23-44 —NHCOCH₂Me

226-227 23-45 —NHCOMe

217-219 23-46 —NHCOCH₂Me

228-229 23-47 —NHCOMe

235-236 23-48 —NHCOCH₂Me

239-241 23-49 —NHCOMe

290-293 23-50 —NHCOCH₂Me

289-290 23-51 —NHCOMe

287-289

TABLE 11

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-52 —NHCCCH₂Me

258-260 23-53 —NHCOMe

317-320 23-54 —NHCOCH₂Me

257-259 23-55 —NHCOMe

308-309 23-56 —NHCOCH₂Me

249-250 23-57 —NH₂

228-230 23-58 —NH₂

231-232 23-59 —NH₂

256-258 23-60 —NH₂

255-258 23-61 —NH₂

>300 23-62 —NH₂

296-298 23-63 —N═C(Me)NMe₂

129-131 23-64 —NHCOMe

282-284 23-65 —NHCOMe

236-239 23-66 —NHCOCH₂Me

222-224 23-67

236-239

TABLE 12

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-68 —NHCOMe

234-236 23-69 —NHCOCH₂Me

237-239 23-70

220-222 23-71 —NHCOMe

294-297 23-72 —NHCOCH₂Me

267-269 23-73 —N(CH₂Me)COMe

143-144 23-74 —N((CH₂)₄Me)COMe

111-113 23-75

162-164 23-76 —NH₂

206-209 23-77 —NH₂

232-234 23-78 —NH₂

236-239 23-79 —NH₂

232-235 23-80

287-289 23-81

330-333 23-82

292-294

TABLE 13

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-83

346-348 23-84

308-310 23-85 —NH₂

323-326 23-86 —NHCOMe

259-261 23-87 —NHCOMe

292-293 23-88

161-163 23-89 —NH₂

235-237 23-90 —NHCOMe

254-257 23-91

274-277 23-92 —NHCOMe

237-239 23-93 —NHCOMe

285-287 23-94 —NH₂

235—238 23-95 —NHCOMe

272-274 23-96 —NH₂

213-215 23-97 —NHCOMe

259-261 23-98 —NHCO(CH₂)₄Cl

228-229

TABLE 14

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-99  —NHCOMe

254-257 23-100

159-160 23-101

278-281 23-102

295-297 23-103

262-264 23-104

266-269 23-105 —NHCOCHMe₂

227-230 23-106 —NHCOCMe₃

254-256 23-107 —NHCOCH₂CHMe₂

261-262 23-108 —NHCONH(CH₂)₂Me

215-219 23-109 —NH₂

285-288 23-110 —NHCOMe

294-295 23-111 —NHCOMe

206-209 23-112 —NHCOMe

201-203 23-113 —NHCOMe

210-212 23-114 —NHCO(CH₂)₃Cl

191-194 23-115

133-135

TABLE 15

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-116 —NHCO(CH₂)₅Cl

223-225 23-117

351-352 23-118 —NHCOMe

265-267 23-119 —NHCOMe

248-250 23-120 —NHCOMe

295-297 23-121 —NHCO(CH₂)₂COOCH₂Me

261-264 23-122 —NHCO(CH₂)₂COOH

334-336 23-123 —NH₂

267-269 23-124 —NH₂

218-219 23-125 —NH₂

248-250 23-126 —NH₂

273-275 23-127 —NHCOMe

295-296 23-128 —NHCOMe

284-286 23-129 —NHCOMe

289-291

TABLE 16

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive mp/° C. 23-130 —NHCOCHMe₂

284-285 23-131 —NHCOCMe₃

293-295 23-132 —NHCONH(CH₂)₂Me

287-288 23-133 —NH₂

242-244 23-134 —NH₂

309-311 23-135 —CH₂COOCH₂Me

HCl 150-152 23-136

150-151 23-137 —NHCOMe

280-281 23-138 —NHCOCHMe₂

303-304 23-139 —NHCOCMe₃

317-319 23-140 —NHCOMe

342-345 23-141 —NHCOCHMe₂

297-298 23-142 —NHCOCMe₃

313-315 23-143 —NH₂

254-257 23-144 —NH₂

261-264 23-145 —CH₂COOH

135-137 23-146 —CH₂CONHMe

129-130

TABLE 17

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-147 -Me

132-133 23-148 —NHCOMe

256-258 23-149 —NHCOCHMe₂

269-272 23-150

240-242 23-151 —NHCOMe

259-261 23-152 —NHCOMe

237-239 23-153 —NHCOMe

296-298 23-154 —NHCOCHMe₂

285-286 23-155 —NHCOCF₃

260-262 23-156 —NHCONHCH₂Me

224-226 23-157 —NHCONHCH₂Me

181-183 23-158 —NH₂

240-242 23-159 —NH₂

204-206 23-160 —NH₂

178-179 23-161 —NH₂

262-264 23-162 —COOH

141-143 23-163 —NHCOCH₂Me

295-297 23-164

292-294 23-165

326-328

TABLE 18

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-166

326-329 23-167

277-279 23-168

309-311 23-169 —NHCONHCH₂Me

289-292 23-170 —NHCONH(CH₂)₂Me

212-214 23-171 —NHCOCH₂OMe

248-249 23-172 —NHCOMe

228-230 23-173 —NHCOCH₂Me

244-246 23-174 —NHCOCHMe₂

228-229 23-175

204-206 23-176

216-218 23-177

218-220 23-178

251-253 23-179

271-273 23-180 —NHCONHCH₂Me

302-305 23-181 —NHCONH(CH₂)₂Me

190-192 23-182 —NH₂

239-241 23-183 —NH₂

304-306

TABLE 19

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-184 —NHCOMe

328-330 23-185 —NHCOCH₂Me

284-286 23-186 —NHCOCHMe₂

274-275 23-187

295-296 23-188

254-255 23-189

272-273 23-190

262-264 23-191

263-264 23-192 —NHCONHCH₂Me

206-207 23-193 —NHCONH(CH₂)₂Me

208-210 23-194 —NHCOCH₂Me

291-293 23-195 —NHCOCHMe₂

270-272 23-196

226-229 23-197

285-286 23-198

275-278

TABLE 20

Ref. Ex. Compd. R_(a) R_(b) R_(c) mp/° C. 23-199

267-270 23-200

302-304 23-201 —NHCONHCH₂Me

202-203 23-202 —NHCONH(CH₂)₂Me

128-130 23-203 —NHCOCH₂OMe

220-222 23-204 —NH₂

237-240 23-205 —NHCOMe

288-289 23-206 —NHCOCH₂Me

292-293 23-207 —NHCOCHMe₂

253-254 23-208

235-238

TABLE 21

Ref. Ex. Compd. R_(a) R_(b) R_(c) Additive mp/° C. 23-209

300-301 23-210

277-278 23-211

278-280 23-212 —NHCONHCH₂Me

220-224 23-213 —NHCONH(CH₂)₂Me

204-206 23-214 —COOCH₂Me

149-150 23-215 —NHCOCH₂NMe₂

230-231 23-216 —NH₂

167-169 23-217 —NHCOMe

195-197 23-218 —NHCOMe

266-270 23-219 —NH₂

181-185 23-220 —NHCOMe

239-244 23-221 —NHCOMe

HCl 237-242 23-222

248-250

EXAMPLE 1

N-Methyl[5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine

To a solution of N-methylthiourea (484 mg) in acetonitrile (40 mL), wasadded 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.0 g), andthen triethylamine (0.8 mL) was added dropwise to the mixture withstirring. After addition, the resulting mixture was stirred at refluxfor 3 h and the solvent was evaporated. An aqueous saturated solution ofsodium hydrogen carbonate was added to the residue and extracted withethyl acetate. The extracts were washed with water, dried and thesolvent was evaporated. The crystalline residue was recrystallized fromethyl acetate-isopropyl ether to give the title compound (1.2 g, yield80%).

mp 144-145° C.

EXAMPLE 2

[5-Phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine

To a mixture of 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide(2.00 g) and thiourea (432 mg) in acetonitrile (30 mL), was addedtriethylamine (0.80 mL) dropwise and the resulting mixture was stirredat 80° C. for 3 h. The solvent was removed under reduced pressure and anaqueous saturated solution of sodium hydrogen carbonate was added to theresidue. The mixture was extracted with ethyl acetate.

The organic phases were washed with water, dried and concentrated underreduced pressure to give the amorphous title compound (1.10 g, yield84%).

¹H-NMR (CDCl₃) δ: 5.31 (2H, br s), 7. 13-7.29 (6H, m), 7.76 (1H, dt,J=7.8, 1.8 Hz), 8.46 (1H, dd, J=5.0, 1.8 Hz), 8.70 (1H, d, J=1.8 Hz).

EXAMPLE 3

N-[5-Phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]acetamide

To a solution of [5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine (1.10 g,4.34 mmol) in N,N-dimethylacetamide (20 mL) was added acetyl chloride(680 mg, 8.68 mmol) and stirred at 80° C. for 3 h. Water was added tothe reaction mixture and extracted with ethyl acetate twice. Thecombined organic phases were washed with water, dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas recrystallized from chloroform-ethyl ether to give the titlecompound (750 mg, yield 59%).

mp 264-267° C.

EXAMPLE 4

Using 2-bromo-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanonehydrobromide and 2-bromo-2-(3,5-dimethylphenyl)-1-(4-pyridyl)ethanonehydrobromide instead of using 2-bromo-2-phenyl-1-(3-pyridyl)ethanonehydrobromide, the below Example Compounds 4-1 and 4-2 were obtained inthe same manner as described in above Example 2.

Example Compound 4-1:

[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]amine

mp 275-277° C.

Example Compound 4-2:

[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]amine

mp 262-263° C.

EXAMPLE 5

Using[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]amineand [5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]amine insteadof using [5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine, the belowExample Compounds 5-1 and 5-2 were obtained in the same manner asdescribed in above Example 3.

Example Compound 5-1:

N-[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide

mp 245-246° C.

Example Compound 5-2:

N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide

mp 304-308° C.

EXAMPLE 6

2-Ethyl-5-phenyl-4-(3-pyridyl)-1,3-thiazole

Using propanethioamide instead of using N-methylthiourea, the titlecompound was obtained in the same manner as described in the aboveExample 1.

mp 144-145° C.

EXAMPLE 7

4-[5-Phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]butyric acid

A solution of methyl 4-[5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]butyrate(4.1 g), which was obtained in the same manner as described in the aboveExample 1 using 4-(methoxycarbonyl)butanethioamide instead of usingN-methylthiourea, in methanol (15 mL) was added to an 8N aqueous sodiumhydroxide solution (20 mL) and stirred at 80° C. for 2 h. The mixturewas adjusted to pH 6.0 with 2N hydrochloric acid and the product wasextracted with ethyl acetate. The extract was washed with water, driedand the solvent was evaporated. The residue was recrystallized fromethyl acetate to afford the title compound (3.4 g, yield 87%).

mp 141-142° C.

EXAMPLE 8

4-[2-Acetylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine1-Oxide

To a suspension ofN-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (1.0g) in chloroform (30 mL), was added 70% m-chloroperbenzoic acid (0.80g), and the mixture was stirred at room temperature for 1 h. The solventwas removed under reduced pressure, and the residue was treated with anaqueous saturated solution of sodium hydrogen carbonate. The formedcrystalline residue was washed with water, dried and recrystallized fromethanol to obtain the title compound (0.55 g, yield 53%).

mp 332-334° C.

The chemical structures obtained in Examples 1 to 8 are shown in Table22.

TABLE 22

Ex. Compd. R_(a) R_(b) R_(c) 1 —NHMe

2 —NH₂

3 —NHCOMe

4-1 —NH₂

4-2 —NH₂

5-1 —NHCOMe

5-2 —NHCOMe

6 —CH₂Me

7 —(CH₂)₃COOH

8 —NHCOMe

(1) Reference: Example Compound 13-89 50 mg (2) Lactose 34 mg (3) Cornstarch 10.6 mg (4) Corn starch (paste) 5 mg (5) Magnesium stearate 0.4mg (6) Calcium carboxymethyl cellulose 20 mg Total 120 mg

(1) to (6) were mixed in an ordinary manner, and tabletted into tabletsusing a tabletting machine.

EXPERIMENTAL EXAMPLE 1

The following procedures in this Example were carried out according tothe methods described in Molecular Cloning—Cold Spring Harbor Laboratory(1989) or protocol specified by manufacturers.

(1) Cloning of Human Adenosine A₃ Receptor

Cloning of the human adenosine A₃ receptor gene was carried out by thepolymerase chain reaction (PCR) from human brain cDNA. Using 1 ng ofbrain cDNA (Quick-Clone cDNA, TOYOBO, Osaka) as template, PCR wasperformed in DNA Thermal Cycler 480 (Perkin Elmer, Foster, Calif.)(reaction conditions: 35 cycles of 1 min at 95° C., 1 min at 66° C., and2 min at 75° C.) by mixing primers (50 pmol each),5′-CGCCTCTAGACAAGATGCCCAACAACAGCACTGC-3′ [Sequence No. 1] and5′-CGGGGTCGACACTACTCAGAATTCTTCTCAATGC-3′ [Sequence No. 2], which weredesigned referring to nucleotide sequence of adenosine A₃ receptor genereported by Salvatore et. al., (Proc. Natl. Acad. Sci. U.S.A.,90:10365-10369, 1993) and TaKaRa LA PCR Kit Ver.2 (TaKaRa Shuzo Co.Ltd., Kyoto) in a Thermal cycler 480 (Parkin Elmer). The PCR product waselectrophoresed and 1.0 kb DNA fragment was recovered. The DNA fragmentencoding adenosine A₃ receptor was cloned using Original TA Cloning Kit(FUNAKOSHI, Tokyo).

Thus obtained plasmid was digested with Xba I (TaKaRa Shuzo Co. Ltd.,Kyoto), blunted with T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto)and digested with Sal I (TaKaRa Shuzo Co. Ltd., Kyoto) to obtainadenosine A₃ receptor gene fragment.

(2) Construction of Human Adenosine A₃ Receptor Expression Plasmid

The SRα promoter from pTB1411 disclosed in JP-A-5-076385 was ligatedinto the pCI vector (Promega, Tokyo). which was digested with Bgl II(TaKaRa Shuzo Co. Ltd., Kyoto), blunted and digested with EcoRI (TaKaRaShuzo Co. Ltd., Kyoto) subsequently. The resulting plasmid, designatedas pCI-SRα, was then digested with Cla I (TaKaRa Shuzo Co. Ltd., Kyoto)and blunted with T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto). Onthe other hand, pGFP-C1 (TOYOBO, Osaka) was digested with Bsu 36I(DAIICHIKAGAKUYAKUHIN, Tokyo) and the 1.63 kb fragment was recoveredafter the blunting with T4 DNA polymerase to ligate to the pCI-SRαvector using DNA Ligation kit (TaKaRa Shuzo Co. Ltd., Kyoto). Theligation mixture was used to transform E.coli JM109 competent cells(TaKaRa Shuzo Co. Ltd., Kyoto). The resulting plasmid thus obtained wasdesignated as pMSRαneo.

pMSRαneo was digested with EcoRI (TaKaRa Shuzo Co. Ltd., Kyoto), bluntedwith T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto) and then digestedwith Sal I (TaKaRa Shuzo Co. Ltd., Kyoto). After the reaction mixturewas fractionated on agarose gel, the DNA at size of 5.4 kb was ligatedwith adenosine A₃ receptor obtained in the above (1) by using DNALigation kit (TaKaRa Shuzo Co. Ltd., Kyoto). The ligation mixture wasused to transform E.coli JM109 competent cells (TaKaRa Shuzo Co. Ltd.,Kyoto). The plasmid thus obtained was designated as pA3SRα.

(3) Transfection of Adenosine A₃ Receptor Expression Plasmid into CHO(dhfr⁻) and the Expression

CHO (dhfr⁻) cells were grown on Ham's F-12 medium (Nihon Selyaku, Tokyo)supplement with 10% fetal bovine serum (Life Tech Oriental; LifeTechnologies, Inc., Rockville, Md., USA) in a 750 ml Tissue cultureflask (Becton Dickinson, Mt. View, Calif.). The growing cells weretreated with 0.5 g/l trypsin-0.2 g/l EDTA (Life Technologies, Inc.,Rockville, Md., USA) to harvest, washed with PBS (Life Technologies,Inc., Rockville, Md., USA), centrifugated at 1000 rpm for 5 min, andsuspended in PBS. Transfection with pA3SRα into the cell was performedby electroporation using a Bio-Rad/Gene Pulser (Bio-Rad, Tokyo) at 0.25V/960 μF (8×10⁶ cells/10 μg DNA/0.4 cm electrode gap cuvette). Thetransfected cells were transferred into Ham's F-12 medium containing 10%fetal bovine serum, cultivated for 24 hours, harvested, suspended inHam's F-12 media supplement with 10% fetal bovine serum and 500 μg/mlgeneticin (Life Technologies Inc., Rockville, Md., USA) at a celldensity of 10⁴ cells/ml. The cells were plated onto 96 well plates(Becton Dickinson, Mt. View, Calif.) containing Ham's F-12 mediasupplement with 10% fetal bovine serum and 500 μg/ml geneticin (LifeTechnologies Inc., Rockville, Md., USA) at a cell density of 10⁴cells/ml. The geneticin resistant cells thus obtained were furthercultivated on 24 well plates (Becton Dickinson, Mt. View, Calif.) andthe cells expressing adenosine A₃ receptor were selected from them asfollows. The cells were incubated in assay buffer I (HBSS (Wakochemicals, Osaka) containing 0.1% BSA, 0.25 mM PMSF, 1 μg/ml pepstatin,and 20 μg/ml leupeptin) to which was added 50 pM ¹²⁵I-AB-MECA (Amersham)as ligand, for 1 hour, and washed with assay buffer I. The radioactivityassociated with the:.cell was measured in a γ-counter to select A3AR/CHOcells which specifically bind to the ligand.

(4) Cell Membrane Preparation of the Transfectant Expressing AdenosineA₃ Receptor

After A3AR/CHO cells obtained in the above (3) were cultivated in Ham'sF-12 medium containing 10% fetal bovine serum for 2 days, the cells weretreated with PBS plus 0.02% EDTA, centrifuged to collect, resuspended inassay buffer II (50 mM Tris-HCl (pH7.5), 1 mM EDTA, 10 mM MgCl₂, 0.25 mMPMSF, 1 μg/ml pepstatin, and 20 μg/ml leupeptin) and homogenized usingPolytron homogenizer (PT-3000, KINEMATICA AG: 20,000 rpm, 20 sec, 3times). This suspension was centrifuged at 2,000 rpm for 10 min andsupernatant fraction containing cell membranes was obtained. Thesupernatant fraction was ultra-centrifuged at 30,000 rpm (model L8-70M,rotor 70Ti, Beckman) for 1 hour. Thus obtained pellet was resuspended inassay buffer II containing 2 unit/ml adenosine deaminase (BoehrigerMannheim, Tokyo) and incubated at 30° C. for 30 min. The suspension wasultra-centrifuged under the same condition as above and the cellmembrane fraction was obtained as the pellet.

(5) Binding Assays with Adenosine A₃ Receptor

10 nM of [³H]-NECA (Amersham Life Sciences, Inc., Tokyo) as ligand wasadded to the reaction mixture including test compound at variousconcentration and 100 μg/ml of membranes obtained in (4) in assay bufferII. The reaction mixture was incubated for 1 hour at room temperatureand filtrated through the Unifilter GF/C (Packard Instrument Company,Tokyo) to transfer the membrane onto the filter, using Cell Harvester(Packard Instrument Company, Tokyo). The filter was washed three timeswith ice-cold 50 mM Tris-HCl (pH 7.5), and dried. Then, Microscint-0 wasplaced on the filter and radioactivity retained on the filter wasdetermined by Top-Count (Packard Instrument Company, Tokyo). Curve-fitand the concentration that inhibits 50% specific binding (IC₅₀) to themembrane of [³H]-NECA were calculated by program Prizm 2.01 (Graph PadSoftware, San Diego).

TABLE 23 Reference Compound No. IC₅₀ (nM) 10 0.27 13-89 0.55 13-92 0.70

This result shows that the compound (I) has a high affinity foradenosine A₃ receptor.

INDUSTRIAL APPLICABILITY

Since compound (I) containing compounds (Ia), (Ib) and (Ic) has a potentA₃ adenosine receptor antagonistic activity and low toxicity, it isuseful as A₃ adenosine receptor antagonist and can be used as aprophylactic and therapeutic agent for asthma, allergosis, inflammation,Addison's diseases, autoallergic hemolytic anemia, Crohn's diseases,psoriasis, rheumatism, diabetes and so on.

2 1 34 DNA Artificial Sequence primer DNA sequence based on adenosine A3receptor gene sequence 1 cgcctctaga caagatgccc aacaacagca ctgc 34 2 34DNA Artificial Sequence primer DNA sequence based on adenosine A3receptor gene sequence 2 cggggtcgac actactcaga attcttctca atgc 34

What is claimed is:
 1. A method for preventing and/or treating asthma,allergosis or inflammation in a mammal in need thereof, which comprisesadministering to said mammal an effective asthma, allergosis orinflammation treating amount of a compound of the formula:

wherein R¹ represents (i) a hydrogen atom, (ii) a C₁₋₈ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents, (iii) a 5- to14-membered heterocyclic group containing 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen, sulfur and oxygen atoms inaddition to carbon atoms, which group may be substituted by 1 to 5substituents, (iv) an amino which may be substituted by 1 or 2substituents selected from the group consisting of (a) a C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents (b) a C₁₋₆alkylidene group which may be substituted by 1 to 5 substituents, (c) a5- to 14-membered heterocyclic group containing 1 to 4 hetero atomsselected from the group consisting of nitrogen, sulfur and oxygen atomsin addition to carbon atoms, which group may be substituted by 1 to 5substituents, and (d) an acyl of the formula: —(C═O)—R⁵, —(C═O)—OR⁵,—(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ wherein R⁵ is (i′) a hydrogen atom,(ii′) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₄aryl or C₇₋₁₆ aralkyl group which may be substituted by 1 to 5substituents or (iii′) a 5- to 14-membered heterocyclic group containing1 to 4 hetero atoms selected from the group consisting of nitrogen,sulfur and oxygen atoms in addition to carbon atoms, which group may besubstituted by 1 to 5 substituents; R⁶ is a hydrogen atom or C₁₋₆ alkyl;and R⁷ is (i′) a C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₆₋₁₄ aryl or C₇₋₁₆ aralkyl group which may be substitutedby 1 to 5 substituents or (ii′) a 5- to 14-membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur and oxygen atoms in addition to carbon atoms, whichgroup may be substituted by 1 to 5 substituents, (v) a 5-7-memberednon-aromatic cyclic amino optionally containing 1 to 4 hetero atomsselected from the group consisting of nitrogen, sulfur and oxygen atomsin addition to carbon atoms and at least one nitrogen atom, which may besubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₄ aryl or C₁₋₆ alkyl-carbonyl, 5- to 10-memberedheterocyclic group and oxo, or (vi) an acyl of the formula: —(C═O)—R⁵,—(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷ wherein each symbol isas defined above; R² is a pyridyl which may be substituted by 1 to 5substituents; and R³is (i) a pyridyl which may be substituted by 1 to 5substituents or (ii) a C₆₋₁₄ aryl which may be substituted by 1 to 5substituents in which a substituent can form, together with aneighboring substituent, a 4-7-membered non-aromatic carbocyclic ring;wherein the above “substituents” are selected from the group consistingof (1) halogen atoms, (2) C₁₋₃ alkylenedioxy, (3) nitro, (4) cyano, (5)optionally halogenated C₁₋₆ alkyl, (6) optionally halogenated C₂₋₆alkenyl, (7) carboxy C₂₋₆ alkenyl, (8) optionally halogenated C₂₋₆alkynyl, (9) optionally halogenated C₃₋₆ cycloalkyl, (10) C₆₋₁₄ aryl,(11) optionally halogenated C₁₋₈ alkoxy, (12) C₁₋₆ alkoxy-carbonyl-C₁₋₆alkoxy, (13) hydroxy, (14) C₆₋₁₄ aryloxy, (15) C₇₋₁₆ aralkyloxy, (16)mercapto, (17) optionally halogenated C₁₋₆ alkylthio, (18) C₆₋₁₄arylthio, (19) C₇₋₁₆ aralkylthio, (20) amino, (21) mono-C₁₋₆ alkylamino,(22) mono-C₆₋₁₄ arylamino, (23) di-C₁₋₆ alkylamino, (24) di-C₆₋₁₄arylamino, (25) formyl, (26) carboxy, (27) C₁₋₆ alkyl-carbonyl, (28)C₃₋₆ cycloalkyl-carbonyl, (29) C₁₋₆ alkoxy-carbonyl, (30) C₆₋₁₄aryl-carbonyl, (31) C₇₋₁₆ aralkyl-carbonyl, (32) C₆₋₁₄ carbonyl, (33)C₇₋₁₆ aralkyloxy-carbonyl, (34) 5- or 6-membered heterocycle carbonyl,(35) carbamoyl, (36) mono-C₁₋₆ alkyl-carbamoyl, (37) di-C₁₋₆alkyl-carbamoyl, (38) C₆₋₁₄ aryl-carbamoyl, (39) 5- or 6-memberedheterocycle carbamoyl, (40) C₁₋₆ alkylsulfonyl, (41) C₆₋₁₄ arylsulfonyl,(42) formylamino, (43) C₁₋₆ alkyl-carbonylamino, (44) C₆₋₁₄aryl-carbonylamino, (45) C₁₋₆ alkoxy-carbonylamino, (46) C₁₋₆alkylsulfonylamino, (47) C₆₋₁₄ arylsulfonylamino, (48) C₁₋₆alkylcarbonyloxy, (49) C₆₋₁₄ aryl-carbonyloxy, (50) C₁₋₆alkoxy-carbonyloxy, (51) mono-C₁₋₆ alkyl-carbamoyloxy, (52) di-C₁₋₆alkyl-carbamoyloxy, (53) C₆₋₁₄ aryl-carbamoyloxy, (54) nicotinoyloxy,(55) 5- to 7-membered saturated cyclic amino which may be substituted by1 to 3 substituents selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-membered aromatic heterocyclicgroup and oxo, (56) 5- to 10-membered aromatic heterocyclic group and(57) sulfo; X represents a sulfur atom; or a pharmaceutically acceptablesalt thereof, which may be N-oxidized, with a pharmaceuticallyacceptable excipient, carrier or diluent.
 2. A method of claim 1,wherein R¹ is an amino which may be substituted.
 3. A method of claim 1,wherein R¹ is an amino which may be substituted by 1 or 2 acyl of theformula: —(C═O)—R⁵, —(C═O)—OR⁵, —(C═O)—NR⁵R⁶, —(C═S)—NHR⁵ or —SO₂—R⁷. 4.A method of claim 1, wherein R¹ is an amino which may be substituted by1 or 2 acyl of the formula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶.
 5. A method ofclaim 1, wherein R¹ is an amino which may be substituted by 1 or 2 acylof the formula: —(C═O)—R⁵ or —(C═O)—NR⁵R⁶; R² is a pyridyl which may besubstituted by 1 to 5 C₁₋₆ alkyl; and R³ is a C₆₋₁₄ aryl which may besubstituted by 1 to 5 substituents selected from the group consisting ofhalogen atoms, optionally halogenated C₁₋₆ alkoxy and carboxy.
 6. Amethod of claim 1, wherein R¹ is (i) a C₁₋₈ alkyl, C₃₋₆ cycloalkyl orC₆₋₁₀ aryl group which may be substituted by 1 to 5 substituentsselected from the group consisting of halogen atoms, optionallyhalogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl, optionally halogenatedC₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, hydroxy, hydroxy, amino,mono-C₁₋₆alkylamino, carboxy, C₁₋₆ alkoxy-carbonyl, mono-C₁₋₆alkyl-carbamoyl and C₆₋₁₄ aryl-carbonylamino, (ii) a 5-memberedheterocyclic group, (iii) an amino which may be substituted by 1 or 2substituents selected from the group consisting of (1) C₁₋₆ alkyl, (2)C₆₋₁₄ aryl, (3) C₇₋₁₆ aralkyl, (4) 6-membered group, (5) a C₁₋₆alkyl-carbonyl, C₃₋₆ cycloalkyl-carbonyl, C₆₋₁₄ aryl-carbonyl, C₇₋₁₆aralkyl-carbonyl, C₁₋₆ alkyl-carbamoyl or 5-6-membered heterocyclecarbonyl group which may be substituted by 1 to 3 substituents selectedfrom the group consisting of halogen atoms, C₁₋₆ alkyl, C₁₋₆ alkoxy,carboxy and C₁₋₆ alkoxy-carbonyl, and (6) di-C₁₋₆ alkylamino-C₁₋₆alkylidene, (iv) a 5- or 6-membered non-aromatic cyclic amino which maybe substituted by C₁₋₆ alkyl-carbonyl or oxo, or (v) carboxy; R² is apyridyl which may be substituted by 1 to 3 C₁₋₆ alkyl; and R³ is a C₆₋₁₀aryl which may be substituted by 1 to 3 substituents selected from thegroup consisting of halogen atoms, C₁₋₃ alkylenedioxy, optionallyhalogenated C₁₋₆ alkyl, carboxy C₂₋₆ alkenyl, optionally halogenatedC₁₋₈ alkoxy, hydroxy, C₇₋₁₆ aralkyloxy and C₁₋₆ alkyl-carbonyloxy, inwhich the alkyl group can form, together with a neighboring alkyl group,a 5-membered non-aromatic carbocyclic ring.
 7. A compound of theformula:

wherein R^(1a) is an amino which may be substituted by 1 or 2substituents selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl, C₆₋₁₄ aryl-carbonyl and C₁₋₆ alkyl-carbamoyl; R^(2a) isa phenyl which may be substituted by 1 to 3 substituents selected fromthe group consisting of halogen atoms, optionally halogenated C₁₋₆ alkyland optionally halogenated C₁₋₆ alkoxy; and R^(3a) is a pyridyl, or asalt thereof.
 8. A process for producing of a compound claim 7, whichcomprises reacting a compound of the formula:

wherein Hal represents halogen atoms and other symbols are as defined inclaim 7, or a salt thereof with a compound of the formula:

wherein R^(1a) is as defined in claim 7, or a salt thereof, optionallyin the presence of a base.
 9. A pharmaceutical composition whichcomprises a compound of claim 7.